Alzheimer's disease: the amyloid cascade hypothesis | Science
A prominent example is the “amyloid cascade hypothesis” proposed for Alzheimer’s disease (Hardy and Higgins, 1992).
Alzheimer's disease: The amyloid cascade hypothesis …
(2016) The amyloid cascade hypothesis: are we poised for success or failure? Journal of Neurochemistry, 139 pp. 237-252. .
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.
Alzheimer's disease : The amyloid cascade hypothesis
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, including memory loss, behavioral and psychological symptoms and personality changes. The neuropathological hallmarks of AD are the presence of neuritic (senile) plaques (NP) and neurofibrillary tangles (NFT), along with neuronal loss, dystrophic neurites, and gliosis. Neuritic plaques are extracellular lesions and their main constituent is the amyloid-β42 peptide (Aβ42). Neurofibrillary tangles are intracellular lesions that are mainly composed of hyperphosphorylated Tau protein. In this article, we review the major hypotheses concerning the physiopathology of AD, focusing on the β-amyloid cascade as primary events (supported by the "βaptists") and cytoskeletal abnormalities secondary to the hyperphosphorylation of protein Tau (as advocated by the "Tauists"). We further provide an integrative view of the physiopathology of AD.
Alzheimer’s Disease (AD) is an age-related neurodegenerative disorder which has yet to be fully understood. The amyloid cascade hypothesis (ACH) has played the prominent role in explaining the etiology and pathogenesis of 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. However, ACH has recently come under severe scrutiny as it has been claimed that SPs may be developed independently and might be the effect of the disease rather than the cause of AD. The present review indeed argues that the amyloid cascade is an effect of the disease and not the cause. We argue that excitotoxic processes caused by hyperphosphorylation of tau tangles at dendritic spines are the leading cause of the change in energy metabolism leading to apoptosis. We also propose that there are links among metabolism, the deposition of amyloid plaques, hyperphosphorylation of tau, and the decline of cognitive functions, following the increase of intraspinal cAMP that we claim is associated with decline of lactate.
Alzheimer's Disease: The Amyloid Cascade Hypothesis
...n. This observation, in the mid1980s (Glenner and Wong, 1984; Masters et al., 1985), led to the hypothesis that deposition of amyloid is an early step in the pathogenesis of AD (Masters et al., 1985; =-=Hardy and Higgins, 1992-=-; Masters and Beyreuther, 1993; Selkoe, 1989) and is in some way associated with the neurodegeneration in AD. This hypothesis gained further credence upon the observations that SP are surrounded by de...
...sis on the etiopathogenesis of AD is the Amyloid Cascade Hypothesis, according to which the generation of A is the primary pathological event which leads to neurofibrillary degeneration and dementia =-=[43, 44]-=-. Consistent with this hypothesis, both intracerebral infusion of A in FTDP-17 tau mutation P301Lexpressing transgenic mice, as well as crossing these animals with APPTg2576 (APP Swedish plus London ...
Alzheimer's disease: the amyloid cascade hypothesis
Perspectives Alzheimer's disease: the amyloid cascade hypothesis
the amyloid cascade hypothesis
Alzheimer's Disease and the Amyloid Cascade Hypothesis…
Title: Alzheimer's Disease: The Amyloid Cascade Hypothesis: Authors: Hardy, John A.; Higgins, Gerald A
Alzheimer's disease: the amyloid cascade hypothesis …
Alzheimer's disease: the amyloid cascade hypothesis ..
the amyloid cascade hypothesis.
Over the last few years, and particularly since the identification of pathogenic mutations, the amyloid cascade hypothesis (Glenner and Murphy, 1989; Hardy and Higgins, 1992) has become the dominant hypothesis for the etiology and pathogenesis of Alzheimer’s disease (AD). In the last two years, much work based on the cascade hypothesis has been published which offers more support for it as a framework for the development of an understanding of the disease. However, the amyloid cascade hypothesis has been extensively criticized on many grounds, some valid and some probably specious. More worrisome, it remains, at best, a mere framework of understanding. In this article, we review recent advances in our understanding of the disease (Progress), outline and discuss some of the criticisms of the cascade hypothesis (Problems) and point to some of the many gaping holes in our knowledge of the disease with respect to this hypothesis (Deficiencies).
Amyloid cascade hypothesis along with evidence of ..
Its objectives are to (1) review the link between Alzheimer’s dementia and fibrillogenic proteins and show that pathogenesis truly involves Aβ; (2) show how key problems in the amyloid cascade hypothesis disappear with the discovery of subfibrillar Aβ assemblies; (3) discuss cellular mechanisms of the new toxins that explain why AD is a disease of memory loss; (4) consider data that clinically substantiate a new, oligomerinitiated amyloid cascade hypothesis; (5) assess whether the impact of subfibrillar toxins can provide a broad mechanism applicable to multiple fibrillogenic proteins; (6) evaluate emerging implications for therapeutics and diagnostics.
At present, no cause for AD has been established; there are no effective therapeutics, and no clinical diagnostics exist.
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