Amyloid fibril formation plays a central role in the pathogenesis of a number of neurodegenerative diseases, including Alzheimer and Parkinson diseases. Transient prefibrillar oligomers forming during the aggregation process, exhibiting a small size and a large hydrophobic surface, can aberrantly interact with a number of molecular targets on neurons, including the lipid bilayer of plasma membranes, resulting in a fatal outcome for the cells. By contrast, the mature fibrils, despite presenting generally a high hydrophobic surface, are endowed with a (...) low diffusion rate and poorly penetrate the interior of the lipid bilayer. However, increasing evidence shows that both intracellular α‐synuclein fibrils, as well and as extracellular amyloid‐β and β2‐microglobulin fibrils, can release oligomers over time that quickly diffuse to reach the membrane of the neighboring cells. The persistent leakage of harmful oligomers from fibrils triggers an ongoing cascade of events resulting in a sustained injury to neurons and glia and also provides aggregates with the ability to cross biological membranes and diffuse between cells or cellular compartments. (shrink)

The apolipoprotein E gene plays an important role in the pathogenesis of Alzheimer's disease , and amyloid plaque comprised mostly of the amyloid-beta peptide ) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-B in APOE gene regulation. To delineate NF-B's role, we have characterized a 1098 nucleotide segment (...) containing the 5'-flanking region of the human APOE gene . Sequence analysis of this region suggests the presence of two potential NF-B elements. To demonstrate promoter activity, the region was cloned upstream of a promoterless luciferase gene. This segment was able to drive expression of luciferase in transient transfections of human fetal glial cells. Promoter activity was stimulated twofold by A treatment. Pretreatment with double-stranded DNA decoy oligonucleotides against NF-B reduced A stimulation. Deletion and mutagenetic analyses demonstrated that the distal NF-B element was functional and showed a strong DNA-protein complex band in gel shift analysis, similar to that from control NF-B consensus element. An anti-inflammatory and anti-NF-B drug, sodium salicylate, significantly blocked A-induced APOE promoter function. Our data provide evidence that upregulation of APOE by A in astroglial cells is mediated by an NF-B-element present in the 5'-flanking region of the APOE gene. (shrink)

A new therapeutic approach is being developed for the treatment of Alzheimer's disease (AD). This approach involves the deliberate induction of an autoimmune response to amyloid‐β (Aβ) peptide, the constituent of neuritic plaques that is thought to cause the neurodegeneration and dementia in AD. If this approach is to be effective, antibodies must be produced that can selectively target the toxic forms of Aβ, while leaving the functionally‐relevant forms of Aβ and its precursor protein untouched. Furthermore, an approach needs (...) to be found that avoids provoking an acute neuroinflammatory response. The situation is made even more challenging by uncertainty regarding which isoforms of Aβ contribute to the pathogenesis of AD. BioEssays 25:283–288, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

A new therapeutic approach is being developed for the treatment of Alzheimer's disease (AD). This approach involves the deliberate induction of an autoimmune response to amyloid‐β (Aβ) peptide, the constituent of neuritic plaques that is thought to cause the neurodegeneration and dementia in AD. If this approach is to be effective, antibodies must be produced that can selectively target the toxic forms of Aβ, while leaving the functionally‐relevant forms of Aβ and its precursor protein untouched. Furthermore, an approach needs (...) to be found that avoids provoking an acute neuroinflammatory response. The situation is made even more challenging by uncertainty regarding which isoforms of Aβ contribute to the pathogenesis of AD. BioEssays 25:283–288, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Substantial evidence implicates fast axonal transport (FAT) defects in neurodegeneration. In Alzheimer's disease (AD), it is controversial whether transport defects cause or arise from amyloid‐β (Aβ)‐induced toxicity. Using a novel, unbiased genetic screen, Morihara et al. identified kinesin light chain‐1 splice variant E (KLC1vE) as a modifier of Aβ accumulation. Here, we propose three mechanisms to explain this causal role. First, KLC1vE reduces APP transport, leading to Aβ accumulation. Second, reduced transport of APP by KLC1vE triggers an ER stress (...) response that activates the amyloidogenic pathway. Third, KLC1vE impairs transport of other KLC1 cargos that regulate amyloidogenesis, promoting Aβ retention within the secretory pathway. Collectively, KLC1vE perpetuates a vicious cycle of Aβ generation, kinase dysregulation, and global FAT impairment that inevitably leads to cellular toxicity. These concepts implicate alternative splicing of KLC1 in AD and suggest that the reciprocal influence of transport mechanisms on disease states contributes to neurodegeneration. (shrink)

BackgroundResearchers currently are not obligated to share individual research results with participants. This non-disclosure policy has been challenged on the basis of participants’ rights to be aware and in control of their personal medical information. Here, we determined how patients view disclosure of research PET results of brain amyloid and why they believe it is advantageous or disadvantageous to disclose.MethodAs a part of a larger diagnostic trial, we conducted semi-structured interviews with patients with amnestic Mild Cognitive Impairment. Participants had (...) the option to receive their brain amyloid PET scan result. Interviews were conducted before they received their IRR.ResultsA total of 38 aMCI patients wanted to know their IRR. The two most frequently mentioned reasons for choosing IRR disclosure were to better understand their brain health status and to be better able to make informed decisions about future personal arrangements. Emotional risk was mentioned as the primary disadvantage of knowing one’s IRR. On the other hand, non-disclosure was considered to be emotionally difficult also, as patients would be uncertain about their future health condition.ConclusionsMany patients diagnosed clinically with aMCI want to know their brain amyloid test results, even though this knowledge may be disadvantageous to them. Knowing what is going on with their health and the ability to make informed decisions about their future were the two principal advantages mentioned for obtaining their amyloid PET results. Because of the overwhelming consensus of aMCI patients was to disclose their brain amyloid PET scan results, researchers should strongly consider releasing this information to research subjects. (shrink)

Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC conjugated (...) Abeta1-40 localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (shrink)

BackgroundStory recall tests have shown variable sensitivity to rate of cognitive decline in individuals with Alzheimer’s disease biomarkers. Although SR tasks are typically scored by obtaining a sum of items recalled, item-level analyses may provide additional sensitivity to change and AD processes. Here, we examined the difficulty and discrimination indices of each item from the Logical Memory SR task, and determined if these metrics differed by recall conditions, story version, lexical categories, serial position, and amyloid status.Methodsn = 1,141 participants (...) from the Wisconsin Registry for Alzheimer’s Prevention longitudinal study who had item-level data were included in these analyses, as well as a subset of n = 338 who also had amyloid positron emission tomography imaging. LM data were categorized into four lexical categories, and by serial position. We calculated difficulty and discriminability/memorability by item, category, and serial position and ran separate repeated measures ANOVAs for each recall condition, lexical category, and serial position. For the subset with amyloid imaging, we used a two-sample t-test to examine whether amyloid positive and amyloid negative groups differed in difficulty or discrimination for the same summary metrics.ResultsIn the larger sample, items were more difficult in the delayed recall condition across both story A and story B. Item discrimination was higher at delayed than immediate recall, and proper names had better discrimination than any of the other lexical categories or serial position groups. In the subsample with amyloid PET imaging, proper names were more difficult for Aβ+ than Aβ−; items in the verb and “other” lexical categories and all serial positions from delayed recall were more discriminate for the Aβ+ group compared to the Aβ− group.ConclusionThis study provides empirical evidence that both LM stories are effective at discriminating ability levels and amyloid status, and that individual items vary in difficulty and discrimination by amyloid status, while total scores do not. These results can be informative for the future development of sensitive tasks or composite scores for early detection of cognitive decline. (shrink)

Most prions (infectious proteins) are self‐propagating amyloids (filamentous protein multimers), and have been found in both mammals and fungal species. The prions [URE3] and [PSI+] of yeast are disease agents of Saccharomyces cerevisiae while [Het‐s] of Podospora anserina may serve a normal cellular function. The parallel in‐register beta‐sheet structure shown by prion amyloids makes possible a templating action at the end of filaments which explains the faithful transmission of variant differences in these molecules. This property of self‐reproduction, in turn, allows (...) these proteins to act as de facto genes, encoding heritable information. BioEssays 30:955–964, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Detection of Alzheimer’s disease in an early stage is receiving increasing attention for a number of reasons, such as the failure of drug trials in more advanced disease stages, the demographic evolution, the financial impact of AD, and the approval of amyloid tracers for clinical use. Five focus group interviews with stakeholders were conducted.. The verbatim transcripts were analysed via the Nvivo 11 software. Most stakeholder groups wanted to know their own amyloid PET scan result. However, differences occurred (...) between FGs: two groups wanted to know, whilst in the three other groups FG members opted not to know or were still in doubt about their decision. Stakeholders provided insight into their reasons for wanting to know their amyloid PET scan result, for not wanting to know their result, or why they were in doubt about their decision. Several advantages and disadvantages were mentioned as part of knowing their amyloid PET scan result. Certain considerations were clustered in a grey zone, in between advantage and disadvantage, such as the emotional consequences. Clinicians, researchers, and policymakers ought to be aware of the diversity of reasons for wanting to know their result and how possible benefits and risks can be viewed differently. The current findings are of importance for future early diagnosis and disclosure of results in the research setting. (shrink)

Given the past two decades of over 40 failed trials of amyloid-lowering therapies in Alzheimer’s Disease (AD), many of which succeeded in lowering amyloid as designed, we present an ethical argument for emptying the drug pipeline of tests of amyloid-lowering agents so as to end the historical dominance of the amyloid-reducing therapeutic approach in AD.

Emerging evidence supports the role for the intracellular domains of amyloid precursor protein (APP) in the physiology and function of APP. In this short report, I discuss the hypothesis that mutation of Tyr682 on the Y682ENPTY687 C‐terminal motif of APP may be directly or indirectly associated with alterations in APP functioning and activity, leading to neuronal defects and deficits. Mutation of Tyr682 induces an early and progressive age‐dependent cognitive and locomotor decline that is associated with a loss of synaptic (...) connections, a decrease in cholinergic tone, and defects in NGF signaling. These findings support a model in which APP‐C‐terminal domain exerts a pathogenic function in neuronal development and decline, and suggest that Tyr682 potentially could modulate the properties of APP metabolites in humans. (shrink)

Amyloid β peptide (βA4) accumulates as plaques in the brains of individuals with Alzheimer's disease and Down's syndrome, and may contribute to the cognitive decline that is a feature of these diseases. βA4 is a normal product of cell metabolism, derived from the amyloid precursor protein (APP), but the biological functions of these molecules are not fully known. A hypothetical, descriptive model of the biological interrelationships between βA4 and APP is presented. APPS, the soluble form of APP, which (...) is released at the neuronal surface, and βA4 are envisaged as physiological ligands which have reciprocal paracrine effects on neuronal growth and neurite extension. Differential expression of these factors, manifest as changes in the APPS:βA4 ratio, may therefore have growth‐promoting or growth‐inhibiting effects on neurons. These effects may be mediated through separate cell‐surface interactions but common intracellular effector systems, such as calcium and protein kinase C. In turn, the intracellular events may control the relative production of each ligand from APP through negative feedback loops. Disturbances of these control mechanisms may permit pathological overproduction, and hence accumulation, of βA4. Such a model may also have therapeutic implications. (shrink)

No cure yet exists for devastating Alzheimer's disease (AD), despite many years and humongous efforts to find efficacious pharmacological treatments. So far, neither designing drugs to disaggregate amyloid plaques nor tackling solely inflammation turned out to be decisive. Mesenchymal stem cells (MSCs) and, in particular, extracellular vesicles (EVs) originating from them could be proposed as an alternative, strategic approach to attack the pathology. Indeed, MSC‐EVs—owing to their ability to deliver lipids/proteins/enzymes/microRNAs endowed with anti‐inflammatory, amyloid‐β degrading, and neurotrophic activities—may (...) be exploited as therapeutic tools to restore synaptic function, prevent neuronal death, and slow down memory impairment in AD. Herein the results presented in the most recently published studies on this topic are critically evaluated, providing a strong rationale for possible employment of MSC‐EVs in AD. (shrink)

The discovery of a novel polypeptide (Islet Amyloid Polypeptide: IAPP) isolated from human and cat islet amyloid and from amyloid of a human insulinoma is reviewed. Structurally, IAPP from the human and cat resembles calcitonin gene‐related peptide (CGRP). The structural similarities between the neuropeptide CGRP and IAPP support the premise that IAPP is hormonal in nature. Our immunohistochemical studies also indicate that normal islet B‐cells of several mammalian species (including man and cat) give strong immunoreactivity with antiserum (...) directed to a synthetic peptide segment of IAPP. The fact that IAPP is deposited as amyloid in the pancreatic islets of type 2 (noninsulin‐dependent) diabetics strongly supports an important but yet unknown link between IAPP and the development of this disease. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from (...) the +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and (...) 5'-untranslated region contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD. (shrink)

Increased amyloid beta (Aβ) production by sequential cleavage of the amyloid precursor protein (APP) by the β‐ and γ‐secretases contributes to the etiological basis of Alzheimer's disease (AD). This process requires APP and the secretases to be in the same subcellular compartments, such as the endosomes. Since all membrane organelles in the endomembrane system are kinetically and functionally linked, any defects in the trafficking and sorting machinery would be expected to change the functional properties of the whole system. (...) The Golgi is a primary organelle for protein trafficking, sorting and modifications, and Golgi defects have been reported in AD. Here we hypothesize that Golgi fragmentation in AD accelerates APP trafficking and Aβ production. Furthermore, Golgi defects may perturb the proper trafficking and processing of many essential neuronal proteins, resulting in compromised neuronal function. Therefore, molecular tools that can restore Golgi structure and function could prove useful as potential drugs for AD treatment. (shrink)

In this article, it is hypothesized that a fundamental chemical reactivity exists between some non‐lipid constituents of cellular membranes and ester‐based lipids, the significance of which is not generally recognized. Many peptides and smaller organic molecules have now been shown to undergo lipidation reactions in model membranes in circumstances where direct reaction with the lipid is the only viable route for acyl transfer. Crucially, drugs like propranolol are lipidated in vivo with product profiles that are comparable to those produced in (...) vitro. Some compounds have also been found to promote lipid hydrolysis. Drugs with high lytic activity in vivo tend to have higher toxicity in vitro. Deacylases and lipases are proposed as key enzymes that protect cells against the effects of intrinsic lipidation. The toxic effects of intrinsic lipidation are hypothesized to include a route by which nucleation can occur during the formation of amyloid fibrils. (shrink)

Recently opposing effects of cysteine protease inhibitors, the human cystatins, on neurodegeneration have been reported. Human cystatin C is a risk factor for late‐onset Alzheimer's disease (AD), whereas human stefin B (cystatin B) has no direct involvement in AD. Conflicting data show that their target protease, cathepsin B, might be anti‐amyloidogenic, helping in amyloid‐beta (Aβ) clearance or, instead, might be involved in Aβ production. Some reports claim that cystatin C binds soluble Aβ, making transgenic animals healthier, others, in contrast, (...) that deleting cystatins genes may contribute to amyloid pathology in animal models of AD. (shrink)

Amyloid beta precursor protein (APP) and prion protein (PrP) are cell membrane elements implicated in neurodegenerative diseases. Both proteins undergo endoproteolysis. Evidence is adduced from the literature hinting that the process in the two proteins could be related, their functions may overlap and their distributions coincide. It is proposed that PrP catalyses its own cleavage, the C-terminal fragment functions as an α secretase and the N-terminal segment chaperones the active site; the α secretase releases anticoagulant and neurotrophic ectodomains from (...) APP. The proposals explain some features of spongiform encephalopathies. BioEssays 23:456–462, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Graphical AbstractYeast prion might be a disease state in most situations, but it might help cells survive under some stress environments.

Cells contain a myriad of membraneless ribonucleoprotein (RNP) condensates with distinct compositions of proteins and RNAs. RNP condensates participate in different cellular activities, including RNA storage, mRNA translation or decay, stress response, etc. RNP condensates are assembled via liquid‐liquid phase separation (LLPS) driven by multivalent interactions. Transition of RNP condensates into bodies with abnormal material properties, such as solid‐like amyloid structures, is associated with the pathogenesis of various diseases. In this review, we focus on how RNAs regulate multiple aspects (...) of RNP condensates, such as dynamic assembly and/or disassembly and biophysical properties. RNA properties – including concentration, sequence, length and structure – also determine the phase behaviors of RNP condensates. RNA is also involved in specifying autophagic degradation of RNP condensates. Unraveling the role of RNA in RNPs provides novel insights into pathological accumulation of RNPs in various diseases. This new understanding can potentially be harnessed to develop therapeutic strategies. (shrink)

Type 2 diabetes mellitus is associated with cognitive impairment in many domains. There are several pieces of evidence that changes in neuronal neuropathies and metabolism have been observed in T2DM. Structural and functional MRI shows that abnormal connections and synchronization occur in T2DM brain circuits and related networks. Neuroplasticity and energy metabolism appear to be principal effector systems, which may be related to amyloid beta deposition, although there is no unified explanation that includes the complex etiology of T2DM with (...) cognitive impairment. Herein, we assume that cognitive impairment in diabetes may lead to abnormalities in neuroplasticity and energy metabolism in the brain, and those reflected to MRI structural connectivity and functional connectivity, respectively. (shrink)

Concerns about the possibility of a sharp rise in the prevalence of Alzheimer’s disease in Western nations have led to both the significant deployment of resources and the development of national research and healthcare plans. Although often focused on treatment, substantial efforts have also been dedicated toward preventing or delaying AD onset. As a result, recent technological and biomedical advances have greatly improved the understanding of AD pathophysiology. While some new tests can assess only risk ), some tests for certain (...) biomarkers (e.g., amyloid beta accumulation in the brain detected via positron... (shrink)

Previously diagnosed by symptoms alone, Alzheimer's disease is now also defined by measures of amyloid and tau, referred to as “biomarkers.” Biomarkers are detectible up to twenty years before symptoms present and open the door to predicting the risk of Alzheimer's disease. While these biomarkers provide information that can help individuals and families plan for long-term care services and supports, insurers could also use this information to discriminate against those who are more likely to need such services. In this (...) article, we evaluate whether state laws prohibit long-term care insurers from making discriminatory or unfair underwriting and coverage decisions based Alzheimer's disease biomarkers status. We report data demonstrating that current state laws do not provide meaningful protections from discrimination by long-term care insurers based on biomarker information. (shrink)

Alzheimer's disease is the most common form of dementia that gradually disrupts the brain network to impair memory, language and cognition. While the amyloid hypothesis remains the leading proposed mechanism to explain AD pathophysiology, anti-amyloid therapeutic strategies have yet to translate into useful therapies, suggesting that amyloid β-protein and its precursor, the amyloid precursor protein are but a part of the disease cascade. Further, risk of AD can be modulated by a number of factors, the most (...) impactful being the ɛ4 isoform of apolipoprotein E. A recent study reported a novel isoform-dependent transcriptional regulation of APP by apoE. These interesting new results add to the myriad of mechanisms that have been proposed to explain how apoE4 enhances AD risk, highlighting the complexities of not only apoE and AD pathophysiology, but also of disease itself. Also see the video abstract here: https://youtu.be/yd14MBdPkCY APP transcription is differentially modulated by apoE and its isoforms: how does this novel mechanism fit with the existing hypotheses? (shrink)

Presenilin‐1 (PS1) is thought to regulate cell differentiation and survival by modulating the Notch signaling pathway. Mutations in PS1 have been shown to cause early‐onset inherited forms of Alzheimer's disease (AD) by a gain‐of‐function mechanism that alters proteolytic processing of the amyloid precursor protein (APP) resulting in increased production of neurotoxic forms of amyloid β‐peptide. The present article considers a second pathogenic mode of action of PS1 mutations, a defect in cellular calcium signaling characterized by overfilling of endoplasmic (...) reticulum (ER) calcium stores and altered capacitive calcium entry; this abnormality may impair synaptic plasticity and sensitize neurons to apoptosis and excitotoxicity. The calcium signaling defect has also been documented in lymphocytes, suggesting a contribution of immune dysfunction to the pathogenesis of AD. A better understanding of the calcium signaling defect resulting from PS1 mutations may lead to the development of novel preventative and therapeutic strategies for disorders of the nervous and immune systems. BioEssays 23:733–744, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Alzheimer's disease results from the degeneration of neurons. Degenerating nerve cells express atypical proteins, and amyloid is deposited. We suggest that some of these events are strongly influenced by genetic factors and age. Animal models should be useful in investigating the pathogenic mechanisms that lead to the brain abnormalities seen in this disease.

Scrapie and Creutzfeldt–Jakob disease (CJD) are caused by prions, which appear to be different from both viruses and viroids. Prions contain protein which is required for infectivity, but no nucleic acid has been found within them. Prion proteins are encoded by a cellular gene and not by a nucleic acid within the infectious prion particle. A cellular homologue of the prion protein has been IDentified. The role of this homologue in metabolism is unknown. Prion proteins, but not the cellular homologue, (...) aggregate into rod‐shaped particles that are histo‐chemically and ultrastructurally IDentical to amyloid. Extracellular collections of prion proteins form amyloid plaques in scrapie‐ and CJD‐infected rodent brains as well as CJD‐infected human brains. Within the plaques, prion proteins assemble to form amyloid filaments. Elucidating the molecular differences between the prion protein and its cellular homologue may be important in understanding the chemical structure and replication of prions. (shrink)

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated (...) in aged monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (shrink)

Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead has been shown to elevate the Alzheimer's disease related beta-amyloid peptide , which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2'-deoxyguanosine levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase in rats developmentally exposed to Pb. Oxo8dG was transiently modulated early in life , but was later elevated 20 months after exposure to (...) Pb had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase , manganese-SOD , and reduced-form glutathion . These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances. (shrink)

Alzheimer's disease (AD) is a neurodegenerative disease exhibiting amyloid beta (Aβ) peptide accumulation as a key characteristic. Autophagy, which is dysregulated in AD, participates in the metabolism of Aβ. Unexpectedly, we recently found that autophagy, in addition to its degradative function, also mediates the secretion of Aβ. This finding adds Aβ to an increasing number of biomolecules, the secretion of which is mediated by autophagy. We also showed that inhibition of Aβ secretion through genetic deletion of autophagy leads to (...) intracellular Aβ accumulation, which enhanced neurodegeneration induced by autophagy deficiency. Hence, autophagy may play a central role in two pathological hallmarks of AD: Aβ amyloidosis and neurodegeneration. Herein, we summarize the role of autophagy in AD with focus on Aβ metabolism in light of the recently established role of autophagy in protein secretion. We discuss potential routes for autophagy‐mediated Aβ secretion and suggest experimental approaches to further elucidate its mechanisms. (shrink)

Accelerated approval of aducanumab for mild Alzheimer's by the U.S. Food and Drug Administration on June 7, 2021, has generated substantial medical, scientific, and ethical controversy. That approval was contrary to the nearly unanimous judgment of the FDA's Advisory Committee that little reliable evidence existed of significant benefit, even though the drug did reduce β‐amyloid. Three major ethical problems were created by this approval: (1) Medicare resources would be unjustly squandered, given the drug's $56,000 annual price and the 3.1 (...) million older potential American patients needing the drug; (2) physicians will feel ethically compelled to provide the drug to desperate, insistent patients, given FDA approval and in spite of side effects of brain bleeds and brain swelling; (3) and false hopes are generated for patients. A needed corrective by the federal government would reduce reimbursement to the bare cost of producing the drug (plus only a modest profit) until a phase IV trial has been successfully completed. (shrink)

Alzheimer's disease is characterized by amyloid-beta peptide -loaded plaques in the brain. Abeta is a cleavage fragment of amyloid-beta protein precursor and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 , which has been shown to be required for the regulation of APP and Abeta. To understand the role of SP1 in APP biogenesis, herein we have characterized the relative distribution (...) and localization of SP1, APP, and Abeta in various brain regions of rodent and primate models using immunohistochemistry. We observed that overall distribution and cellular localization of SP1, APP, and Abeta are similar and neuronal in origin. Their distribution is abundant in various layers of neocortex, but restricted to the Purkinje cell layer of the cerebellum, and the pyramidal cell layer of hippocampus. These findings suggest that overproduction of Abeta in vivo may be associated with transcriptional pathways involving SP1 and the APP gene. (shrink)

Genetic and environmental factors leading to Alzheimer's disease (AD) converge in a pathogenic pathway that leads to the accumulation of mis‐folded amyloid peptide (Aβ) in the brain. Removal of Aβ from the brain has thus been the focus of academic and industrial research in the last decade. The concept of immunization therapy could be proven in animal models mimicking amyloid pathology but a multicenter clinical trial in which AD patients were vaccinated with aggregated Aβ has resulted in somewhat (...) unanticipated and partially conflicting results. The occurrence of meningoencephalitis in 6% of vaccinated individuals forced the discontinuation of the clinical study, preventing the generation of sufficient data for an unequivocal statement about the effectiveness of such a therapy approach. This study, however, clearly showed that vaccination induced the production of antibodies against Aβ in some immunized patients. Moreover, circulating anti‐Aβ antibodies are found in healthy humans suggesting a protective role of such physiological antibodies. Nonetheless, the physiological role of the immune system in preventing AD is not fully understood. This article summarizes crucial animal and clinical data underscoring the potential of the immune system for AD treatment. BioEssays 29:927–932, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Demystifying the Mystery of Alzheimer's as Late, No Longer Mild Cognitive ImpairmentPeter J. Whitehouse (bio)Keywordsaging, Alzheimer’s disease, deconstruction, mild cognitive impairmentProfessor Tom Kirkwood and Michael Bavidge's comments are welcome additions to our discourse as both emphasize the importance of considering mild cognitive impairment (MCI) and Alzheimer's disease (AD) in relationship to the normal biological and cultural processes of aging. Whereas I agree with my colleague and co-author, Atwood Gaines' (...) response, I wish to add my own commentary to update the reader concerning the dynamic political processes at work in the social construction and deconstruction of MCI and AD. I have referred to MCI as autodeconstructing AD because whatever we come to think of the MCI label on the spectrum of cognitive aging should alter our beliefs about the ultimate utility of the concept of AD. Tensions in the field of study of MCI have increased since the project reported in this journal began. The social science and philosophical contributions toward understanding MCI need to inform our debate now; otherwise, we will be less effective at influencing a critical debate for society about its relationships to medicine, science, and modern capitalism.This past year, Ron Petersen, the major proponent of the concept of MCI was awarded the prestigious Potamkin Prize for research in Alzheimer's disease by the American Academy of Neurology. The National Institute on Aging (NIA) placed the discovery of MCI as first on the list of contributions during twenty years of research funded through hundreds of millions of dollars poured into the NIA Alzheimer's Research Centers. Some have even suggested that we relabel MCI of the amnestic type, Petersen syndrome. Yet, John Morris, who was co-awarded the Potamkin Prize, has continued to write that MCI is early AD and most recently has suggested (Morris 2006) that we should revise our diagnostic criteria. He joins me and a growing list of other so-called thought leaders who believe (but do not always state publicly) that the term MCI is not useful clinically. Lon Schneider (2005) has recently joined the camp of critics publicly by suggesting that MCI is [End Page 87] not only confusing clinically but is now possibly retarding research.The proliferation of different kinds of MCI indicates that we are studying heterogeneous processes of brain aging. Whereas, John Morris suggests that we relabel MCI as early AD, I have suggested the converse. For example, in a grand rounds lecture at Johns Hopkins in March 2004, I used the lecture title "LNLMCI (late no longer MCI)" as a synonym for AD.Kirkwood is right to compare the quest for biological therapy for AD to the search to treat aging processes in other organs. He has been an outspoken critic of anti-aging medicine quackery that claims that aging itself is a disease that can be reversed today. But, if AD is brain aging, are we not in fact creating a "disease" category that raises false hopes and expectations?Kirkwood also points out that aging is a lifespan process. To prevent dementia in older individuals, we should prevent damage to neurons in younger individuals. Recently, it has been claimed, for example, that exposure to lead in young animals makes these animals more at risk for amyloid deposition in later life (Basha et al. 2005). Whether or not lead directly affects the pathogenesis of AD, it seems eminently reasonable to try to prevent damage to neurons in young children so that they may have maximum cognitive capacity throughout their lifespan.Almost ten years ago, when I stepped down as the editor of the Alzheimer's Disease and Associated Disorders Journal and as John Morris took over this responsibility, I wrote an editorial calling for the end of AD (Whitehouse 2001). In other words, I argued that thinking through the invention of the term mild cognitive impairment reveals that we are attempting to assign medical categories to what are a heterogeneous set of processes that affect our brains as we age. At the hundredth anniversary of the first case of what we have come to call Alzheimer's disease, perhaps it is time to reflect on the individual and social... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Mild Cognitive Impairment, and the Biology of Intrinsic AgingThomas B. L. Kirkwood (bio)Keywordsaging, Alzheimer’s disease, genetic mutation, mild cognitive impairment, telomereThe article by Gaines and Whitehouse (2006) raises key questions about the uncertain relationship between (i) the intrinsic, "normal" aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This short commentary offers a perspective on this (...) debate that is drawn from a consideration of underlying biological mechanisms.Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there is no active program for aging and that there are no genetic factors that have evolved specifically to cause aging or age-related diseases. Unquestionably, there are genes that influence susceptibility to disease and even length of life, but these genes are genes for maintenance and repair functions, not for aging. It is the limitation in the past evolutionary pressure to invest in greater longevity than was required, within an environment where life was usually truncated by hazards such as starvation, injury, or infection, that means that our maintenance systems—good as they are—are insufficient to keep us going indefinitely. Added to this is the idea that there are probably also genes that program processes that are good for the young organism, but which may in later life have harmful effects. Processes like inflammation and apoptosis, which are seen to occur extensively in aged tissues, including brain, surely evolved to help cope with infection and cellular damage arising earlier in life. That they are called into play in aged tissues is a direct, but secondary, consequence of accumulated damage.With this general framework to understand the intrinsic biology of aging, let us now ask what we might expect a priori for the aging of an organ such [End Page 79] as the brain. Although we cannot pretend complete ignorance of how the brain actually does age, our enquiry can be based entirely on data from other organ systems, so we can develop our predictions about brain aging without prejudice.Aging begins very early during human development, faults accumulating from the first stages of embryonic development. Each time a cell divides, each of the daughter cells is likely to acquire a few new mutations. We know this from the estimates for the error rate in DNA replication and the size of the human genome. It is confirmed by direct evidence that at individual gene loci where mutations have been measured, mutation frequency increases with age (Morley 1998; Vijg 2000). In addition to replication errors, DNA is damaged on a daily basis to a very considerable degree by agents such as reactive oxygen species (free radicals), which are formed as byproducts of normal cellular metabolism. Although most of this damage is corrected by repair, the repair mechanisms themselves are not error free and additional mutations accumulate through this route. If a mutation is lethal to the cell, the cell dies and thus the mutation is eliminated. However, the majority of mutations are nonlethal, either because the mutation is recessive and the cell carries an intact gene copy on the other chromosome, because the gene is not currently required, or because the mutation produces only a delayed deleterious effect. Examples of genes that produce delayed deleterious effects include the genes responsible for familial AD. It is interesting to reflect that on statistical grounds alone, it is almost certain that each of us carries a randomly determined fraction of cells in our brains that bear amyloid precursor protein or presenilin mutations associated with AD. We also carry a heterogeneous array of random mutations that compromise essential cell maintenance functions. How many such... (shrink)

Neither the pathogenesis nor the aetiology of Down's syndrome (DS) are clearly understood. Numerous studies have examined whether clinical features of DS are a consequence of specific chromosome 21 segments being triplicated. There is no evidence, however, that individual loci are responsible, or that the oxidative damage in DS could be solely explained by a gene dosage effect. Using astrocytes and neuronal cultures from DS fetuses, a recent paper shows that altered metabolism of the amyloid precursor protein and oxidative (...) stress result from mitochondrial dysfunction.1 These findings are consistent with considerable data implicating the role of the mitochondrial genome in DS pathogenesis and aetiology. BioEssays 24:681–684, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

In Gustavsson et al,1 we discussed the ethical issues that arise when identifying the relevant population for disease-modifying drugs targeting Alzheimer disease. More specifically, we focused on novel immunotherapies aimed at amyloid β and tau, two relevant biomarkers. The commentaries to our paper2 3 acknowledge our conclusion: screening for AD involve ethical costs that cannot be justified unless a drug with clinically relevant effect becomes available. Since Aduhelm is the only immunotherapy targeting AD currently approved by the Food and (...) Drug Administration, we use that as a …. (shrink)

The present review highlights an association between autism, Alzheimer disease , and fragile X syndrome . We propose a conceptual framework involving the amyloid-beta peptide , Abeta precursor protein , and fragile X mental retardation protein based on experimental evidence. The anabolic effect of the secreted alpha form of the amyloid-beta precursor protein may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with more severe (...) symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 . Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPalpha level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPalpha and production of insoluble Abeta would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. (shrink)

Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta (...) amyloid precursor cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

Alzheimer’s disease is an example of age-related dementia, and there are still no known preventive or curative measures for this disease. Obesity and associated metabolic changes are widely accepted as risk factors of age-related cognitive decline. Insulin is the prime mediator of metabolic homeostasis, which is impaired in obesity, and this impairment potentiates amyloid-β accumulation and the formation of neurofibrillary tangles. Obesity is also linked with functional and morphological alterations in brain mitochondria leading to brain insulin resistance and memory (...) deficits associated with AD. Also, increased peripheral inflammation and oxidative stress due to obesity are the main drivers that increase an individual’s susceptibility to cognitive deficits, thus doubling the risk of AD. This enhanced risk of AD is alarming in the context of a rapidly increasing global incidence of obesity and overweight in the general population. In this review, we summarize the risk factors that link obesity with AD and emphasize the point that the treatment and management of obesity may also provide a way to prevent AD. (shrink)

Cognitive dysfunction in Alzheimer’s disease is caused by disturbances in neuronal circuits of the brain underpinned by synapse loss, neuronal dysfunction and neuronal death. Amyloid beta and tau protein cause these pathological changes and enhance neuroinflammation, which in turn modifies disease progression and severity. Vagal nerve stimulation, via activation of the locus coeruleus, results in the release of catecholamines in the hippocampus and neocortex, which can enhance synaptic plasticity and reduce inflammatory signalling. Vagal nerve stimulation has shown promise to (...) enhance cognitive ability in animal models. Research in rodents has shown that VNS can have positive effects on basal synaptic function and synaptic plasticity, tune inflammatory signalling, and limit the accumulation of amyloid plaques. Research in humans with invasive and non-invasive VNS devices has shown promise for the modulation of cognition. However, the direct stimulation of the vagus nerve afforded with the invasive procedure carries surgical risks. In contrast, non-invasive VNS has the potential to be a broadly available therapy to manage cognitive symptoms in early AD, however, the magnitude and specificity of its effects remains to be elucidated, and the non-inferiority of the effects of non-invasive VNS as compared with invasive VNS still needs to be established. Ongoing clinical trials with healthy individuals and patients with early AD will provide valuable information to clarify the potential benefits of non-invasive VNS in cognition and AD. Whether invasive or non-invasive VNS can produce a significant improvement on memory function and whether its effects can modify the progression of AD will require further investigation. (shrink)

Background: Today, many healthcare or dementia organizations, clinicians, and companies emphasize the importance of detection of Alzheimer’s disease in an early phase. This idea has gained considerable momentum due to the development of biomarkers, the recent FDA and EMA approval of three amyloid tracers, and the failure of a number of recent therapeutic trials conducted in the early dementia phase. On the one hand, an early etiological diagnosis can lead to early and more efficacious intervention. On the other hand, (...) it is questioned how early an etiological diagnosis is beneficial to the patient. Here we consider ethical issues related to the process of biomarker testing and the impact on the diagnostic disclosure to patients with mild cognitive impairment due to prodromal Alzheimer’s disease. Methods: A systematic review of the theoretical bioethics literature was performed by using electronic databases. The review was limited to articles published in English between 2003 and 2016. Results: A total of twenty articles were included in our effort to make an analysis of the ethical challenges. One of the biggest challenges was the uncertainty and the predictive value of the biomarker-based diagnosis where patients can be amyloid positive without full certainty whether or when they will develop symptomatic decline due to Alzheimer’s disease. Another challenge was the tension between the right to know versus the wish not to know, the limited efficacy of currently available treatment options, and the opportunities and consequences after receiving such an early diagnosis. Conclusion: Based on the results and the additional comments in the discussion, several unanswered questions emerged. Therefore, careful consideration of all these ethical issues is required before the disclosure of a biomarker-based diagnosis to the patient with mild cognitive impairment due to Alzheimer’s disease. (shrink)