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The Pathogenesis of Alzheimer's Disease: A Reevaluation of the “Amyloid Cascade Hypothesis”
R. A. Armstrong
International Journal of Alzheimer's Disease , 2011, DOI: 10.4061/2011/630865
Abstract: The most influential theory to explain the pathogenesis of Alzheimer's disease (AD) has been the “Amyloid Cascade Hypothesis” (ACH) first formulated in 1992. The ACH proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs) death of neurons, and ultimately dementia. This paper examines two questions regarding the ACH: (1) is there a relationship between the pathogenesis of SPs and NFTs, and (2) what is the relationship of these lesions to disease pathogenesis? These questions are examined in relation to studies of the morphology and molecular determinants of SPs and NFTs, the effects of gene mutation, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies, and the degeneration of anatomical pathways. It was concluded that SPs and NFTs develop independently and may be the products rather than the causes of neurodegeneration in AD. A modification to the ACH is proposed which may better explain the pathogenesis of AD, especially of late-onset cases of the disease.
Advances in the pathogenesis of Alzheimer’s disease: a re-evaluation of amyloid cascade hypothesis
Dong Suzhen,Duan Yale,Hu Yinghe,Zhao Zheng
Translational Neurodegeneration , 2012, DOI: 10.1186/2047-9158-1-18
Abstract: Alzheimer’s disease (AD) is a common neurodegenerative disease characterized clinically by progressive deterioration of memory, and pathologically by histopathological changes including extracellular deposits of amyloid-beta (A-beta) peptides forming senile plaques (SP) and the intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau in the brain. This review focused on the new developments of amyloid cascade hypothesis with details on the production, metabolism and clearance of A-beta, and the key roles of some important A-beta-related genes in the pathological processes of AD. The most recent research advances in genetics, neuropathology and pathogenesis of the disease were also discussed.
Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade  [PDF]
Huntington Potter,Thomas Wisniewski
International Journal of Alzheimer's Disease , 2012, DOI: 10.1155/2012/489428
Abstract: The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE). Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment. 1. Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder that is clinically characterized by progressive mental decline and histopathologically defined by highly abundant amyloid deposits and neurofibrillary tangles in the brain parenchyma. The identification of mutations within the amyloid precursor protein (APP) and presenilin (PS) genes that cause autosomal dominantly inherited AD and that result in increased production of amyloid-prone forms of Aβ established beyond doubt that the processing of APP and the production of Aβ peptides are intimately involved in the disease process and led to the proposal and the reinforcement of the Alzheimer Amyloid Cascade Hypothesis [1, 2]. The role of amyloid in neuronal dysfunction has recently been extended by the discovery of small, soluble, oligomers of the Aβ peptide, some forms of which have been termed ADDLs (Aβ-derived diffusible ligands), protofibrils, or Aβ*56 [3–6]. These Aβ oligomers are not only potential intermediates in the formation of amyloid filaments, but they also have been shown to be neurotoxic themselves and to inhibit long-term potentiation (LTP), a cellular model of memory, in hippocampal slices [4, 7, 8]. Thus, the Amyloid Cascade Hypothesis now includes the
Alzheimer's Disease and the Amyloid Cascade Hypothesis: A Critical Review  [PDF]
Christiane Reitz
International Journal of Alzheimer's Disease , 2012, DOI: 10.1155/2012/369808
Abstract: Since 1992, the amyloid cascade hypothesis has played the prominent role in explaining the etiology and pathogenesis of Alzheimer's disease (AD). It proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs), neuronal cell death, and ultimately dementia. While there is substantial evidence supporting the hypothesis, there are also limitations: (1) SP and NFT may develop independently, and (2) SPs and NFTs may be the products rather than the causes of neurodegeneration in AD. In addition, randomized clinical trials that tested drugs or antibodies targeting components of the amyloid pathway have been inconclusive. This paper provides a critical overview of the evidence for and against the amyloid cascade hypothesis in AD and provides suggestions for future directions. 1. Introduction Alzheimer’s disease (AD), which is characterized by progressive deterioration in cognition, function, and behavior, places a considerable burden on western societies. It is the sixth leading cause of all deaths and the fifth leading cause of death in persons aged ≥65 years. To date, an estimated 5.4 million Americans have AD, but due to the baby boom generation, the incidence in 2050 is expected to reach a million persons per year, resulting in a total estimated prevalence of 11 to 16 million affected persons. Since the first description of presenile dementia by Alois Alzheimer in 1907 [1], senile plaques (SPs) and neurofibrillary tangles (NFTs) are considered the key pathological hallmarks of AD [2]. The identification of β-amyloid (Aβ) in SPs [3] and genetic studies that identified mutations in the amyloid precursor protein (APP) [4], presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes [5, 6] leading to the accumulation of Aβ and early-onset familial dementia [4, 5, 7], resulted in the formulation of the “Amyloid Cascade Hypothesis” (ACH; Figure 1) [8, 9]. According to the ACH, the deposition of Aβ is the initial pathological trigger in the disease, which subsequently leads to the formation of NFTs, neuronal cell death and dementia. While there is considerable evidence supporting this hypothesis, there are observations that seem to be inconsistent. This paper summarizes the current evidence for and against the amyloid cascade in AD. Figure 1: Amyloid cascade hypothesis. 2. Amyloid Cascade Hypothesis As described above, two key observations resulted in the original formulation of the ACH (Figure 1). First, the detection of Aβ as a main constituent of the
Can novel therapeutics halt the amyloid cascade?
Niels D Prins, Pieter Visser, Philip Scheltens
Alzheimer's Research & Therapy , 2010, DOI: 10.1186/alzrt28
Abstract: Despite a significant increase in our understanding of the pathogenesis of Alzheimer's disease (AD) over the past two decades, the therapeutic options are still very modest. Cholinesterase inhibitors and the N-methyl-D-aspartate receptor agonists currently available have a modest clinical effect but do not intervene with the underlying pathophysiology [1]. The ultimate aim of AD therapy is to stop or slow down the underlying disease process.Recently the first two large trials with drugs that may slow disease progression have been published: a phase 2, passive immunization trial with bapineuzumab; and a phase 3 trial with tarenflurbil, a modulator of γ-secretase. Both drugs supposedly interfere with β-amyloid (Aβ) metabolism. Abnormalities in Aβ processing are thought to be central in AD pathophysiology according to the amyloid cascade hypothesis. The mode of action of bapineuzumab is to remove aggregated Aβ, while tarenflurbil decreases the production of the pathogenic Aβ42 peptide. In the present commentary, we discuss the results of these trials and the implications for future therapy and insight into AD pathophysiology.The amyloid hypothesis has led to an understanding of the pathology of AD, and also provides a basis for novel drug development. This hypothesis suggests that increased Aβ42 production and subsequent aggregation in limbic and association cortices leads to synaptic changes and causes deposition of Aβ42 in diffuse plaques, which in turn causes microglial and astrocytic activation. As a result, altered neuronal homeostasis and oxidative injury lead to tangle formation, and eventually to neuronal and synaptic dysfunction and selective neuronal loss [2,3]. The most important implied prediction of the hypothesis is that reduction of Aβ aggregation would ameliorate AD symptoms.Three methods for intervening in the amyloid cascade have thus far been tested in clinical trials: active immunization, passive immunization, and modulation of γ-secretase [4,5]. In
A perspective on SIDS pathogenesis. The hypotheses: plausibility and evidence
Paul N Goldwater
BMC Medicine , 2011, DOI: 10.1186/1741-7015-9-64
Abstract: Before committing to this task it is apposite to consider the background and context in which the various hypotheses arose.Beckwith's 1970 definition of SIDS [1] created the presumption that SIDS babies were normal. Questions arose after Kinney et al. [2] developed their hypothesis based on histopathological abnormalities of the brain, a prenatal origin of these and sudden death occurring during a vulnerable period in infancy. Bergman (1970) [3] had argued against a "single characteristic that ordains an infant for death," but for an interaction of risk factors with variable probabilities. This approach was supported by Wedgewood (1972) [4] whose hypothesis consisted of host vulnerability, age-specific risks, and precipitating factors. Others have supported a multifactorial approach (Raring 1975) [5], (Rognum and Saugstag 1993) [6].The triple risk hypothesis of Filiano and Kinney (1994) [7] has been popular with its central focus on brainstem prenatal injury in a subset of SIDS, denoting a not universal finding. The National Institute of Child Health and Development SIDS Strategic Plan 2001 [8], stated unequivocally that 'Knowledge acquired during the past decade supports the general hypothesis that infants who die from SIDS have abnormalities at birth that render them vulnerable to potentially life-threatening challenges during infancy.' In essence, this states that SIDS is a developmental disorder originating during fetal development. Interest in the brainstem began with Naeye's (1976) [9] findings of astrogliosis in 50% of SIDS and controls. Hypoxia was considered to be the underlying cause. Kinney et al. (1983) [10] found gliosis in only about one-fifth of SIDS cases. This shortfall stimulated studies on brainstem neurotransmitters [11,12]. Ambler et al. (1981) [13] could not distinguish SIDS from other deaths on the basis of neuropathological findings and concluded that known causes of sudden death were unsuitable as a control group. Considerable debate over th
Bapineuzumab Alters Aβ Composition: Implications for the Amyloid Cascade Hypothesis and Anti-Amyloid Immunotherapy  [PDF]
Alex E. Roher, David H. Cribbs, Ronald C. Kim, Chera L. Maarouf, Charisse M. Whiteside, Tyler A. Kokjohn, Ian D. Daugs, Elizabeth Head, Carolyn Liebsack, Geidy Serrano, Christine Belden, Marwan N. Sabbagh, Thomas G. Beach
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059735
Abstract: The characteristic neuropathological changes associated with Alzheimer’s disease (AD) and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemical assessments of 3 subjects treated with bapineuzumab infusions. Histological analyses were conducted to quantify amyloid plaque densities, Braak stages and the extent of cerebral amyloid angiopathy (CAA). Amyloid-β (Aβ) species in frontal and temporal lobe samples were quantified by ELISA. Western blots of amyloid-β precursor protein (AβPP) and its C-terminal (CT) fragments as well as tau species were performed. Bapineuzumab-treated (Bapi-AD) subjects were compared to non-immunized age-matched subjects with AD (NI-AD) and non-demented control (NDC) cases. Our study revealed that Bapi-AD subjects exhibited overall amyloid plaque densities similar to those of NI-AD cases. In addition, CAA was moderate to severe in NI-AD and Bapi-AD patients. Although histologically-demonstrable leptomeningeal, cerebrovascular and neuroparenchymal-amyloid densities all appeared unaffected by treatment, Aβ peptide profiles were significantly altered in Bapi-AD subjects. There was a trend for reduction in total Aβ42 levels as well as an increase in Aβ40 which led to a corresponding significant decrease in Aβ42:Aβ40 ratio in comparison to NI-AD subjects. There were no differences in the levels of AβPP, CT99 and CT83 or tau species between Bapi-AD and NI-AD subjects. The remarkable alteration in Aβ profiles reveals a dynamic amyloid production in which removal and depositional processes were apparently perturbed by bapineuzumab therapy. Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline.
Microarray Analysis on Human Neuroblastoma Cells Exposed to Aluminum, β1–42-Amyloid or the β1–42-Amyloid Aluminum Complex  [PDF]
Valentina Gatta,Denise Drago,Karina Fincati,Maria Teresa Valenti,Luca Dalle Carbonare,Stefano L. Sensi,Paolo Zatta
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015965
Abstract: A typical pathological feature of Alzheimer's disease (AD) is the appearance in the brain of senile plaques made up of β-amyloid (Aβ) and neurofibrillary tangles. AD is also associated with an abnormal accumulation of some metal ions, and we have recently shown that one of these, aluminum (Al), plays a relevant role in affecting Aβ aggregation and neurotoxicity.
Down's Syndrome with Alzheimer's Disease-Like Pathology: What Can It Teach Us about the Amyloid Cascade Hypothesis?  [PDF]
Rania M. Bakkar,Guangju Luo,Thomas A. Webb,Keith A. Crutcher,Gabrielle M. de Courten-Myers
International Journal of Alzheimer's Disease , 2010, DOI: 10.4061/2010/175818
Abstract: Down's syndrome (DS, trisomy 21) represents a complex genetic abnormality that leads to pathology in later life that is similar to Alzheimer's disease (AD). We compared two cases of DS with APOE 3/3 genotypes, a similar age at death, and comparable amyloid-beta 42 peptide (A 42) burdens in the brain but that differed markedly in the severity of AD-like pathology. One exhibited extensive neurofibrillary pathology whereas the other showed minimal features of this type. Comparable loads of A 42 could relate to the cases' similar life-time accumulation of A due to trisomy 21-enhanced metabolism of amyloid precursor protein (APP). The cases' significant difference in AD-like pathology, however, suggests that parenchymal deposition of A 42, even when extensive, may not inevitably trigger AD-like tau pathology (though it may be necessary). Thus, these observations of a natural experiment may contribute to understanding the nuances of the amyloid cascade hypothesis of AD pathogenesis. 1. Introduction Down’s syndrome (DS), caused by an additional chromosome 21, most commonly underlies genetic mental retardation. Alzheimer’s disease (AD) is the most common neurodegenerative disease causing dementia. DS is a strong risk factor for dementia that is very similar to AD. DS’ prevalence of dementia increases with age: 8% before age of 50, 55% before age of 60, and 75% after age of 60 years. Sporadic AD manifests increasingly after age of 60 years to affect 1 in 4 at age of 85 years [1]. AD-like pathology develops inevitably in DS brains after age of 40 and stages similar to sporadic AD are recapitulated and accelerated in DS brains [2]. The earliest changes in young DS brains (<30 years) consist of intracellular accumulation of amyloid-beta peptide (A ) in neurons and astrocytes, followed by deposition of extracellular A with formation of diffuse plaques and, finally, the appearance of neuritic plaques and neurofibrillary tangles [3]. The A peptide is a product of two sequential cleavages of the receptor-like amyloid precursor protein (APP). The proteases involved are -secretase (identified as the aspartyl protease BACE-1, the beta-site APP-cleaving enzyme) and -secretase, a multimeric complex containing presenilin. Alpha-secretase cleaves within the A polypeptide releasing nonamyloidogenic fragments. Gamma-secretase can release either A or A 42, which has been reported to aggregate more and be cytotoxic. Secreted A can become degraded by metalloproteases or be metabolized through uptake mediated by apolipoprotein E (ApoE) [4–6]. The reason why DS patients in later
Primary age-related tauopathy and the amyloid cascade hypothesis: the exception that proves the rule?  [PDF]
John F. Crary
journal of neurology & neuromedicine , 2016, DOI: https://doi.org/10.29245/2572.942X/2016/6.1059
Abstract: Extensive data supports the amyloid cascade hypothesis, which states that Alzheimer’s disease (AD) stems from neurotoxic forms of the amyloid-beta(Aβ)peptide. But the poor correlation between Aβ plaques and neurodegeneration/cognitive impairment, the spaciotemporal disparity between Aβ and tau pathology, and the disappointing results following several large clinical trials using Aβ-targeting agents are inconsistent with this explanation. The most perplexing inconsistency is the existence of AD-type dementia patients that develop abundant neurofibrillary tangles that are indistinguishable from those in early to moderate-stage AD in the absence of compelling evidence of amyloid toxicity. This neuropathological phenotype, which is distinct from other diseases with tangles, represents a conceptual disconnect, because it does not fall within any previously established category of tauopathy and ostensibly invalidates the amyloid cascade hypothesis. Instead, recent efforts have led to consensus criteria for a new alternative diagnostic category, which presupposes that these tangle-only dementia patients represent extreme examples of a distinct primary age-related tauopathy (PART) that is universally observed, albeit to varying degrees, in the aging brain. The cause of PART is unknown, but sufficient evidence exists to hypothesize that it stems from an Aβ-independent mechanism, such as mechanical injury. Should the PART hypothesis withstand further experimental testing, it would represent a shift in the way a subset of subjects with AD neuropathological change are classified and has the potential to focus and reaffirm the amyloid cascade hypothesis.
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