scholarly journals Alzheimer's Disease and the Amyloid Cascade Hypothesis: A Critical Review

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Christiane Reitz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Randomized Clinical Trials ◽  
Senile Plaques ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Amyloid Cascade Hypothesis ◽  
Amyloid Aβ ◽  
Amyloid Cascade ◽  
Critical Overview

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.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer's Disease

2020 ◽  
Vol 20 (26) ◽  
pp. 2380-2390 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Abdullah Al Mamun ◽  
Md. Ataur Rahman ◽  
Tapan Behl ◽  
Asma Perveen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Misfolded Proteins ◽  
Cell Organelles ◽  
The Impact

Objective: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by the extracellular accumulations of amyloid beta (Aβ) as senile plaques and intracellular aggregations of tau in the form of neurofibrillary tangles (NFTs) in specific brain regions. In this review, we focus on the interaction of Aβ and tau with cytosolic proteins and several cell organelles as well as associated neurotoxicity in AD. Summary: Misfolded proteins present in cells accompanied by correctly folded, intermediately folded, as well as unfolded species. Misfolded proteins can be degraded or refolded properly with the aid of chaperone proteins, which are playing a pivotal role in protein folding, trafficking as well as intermediate stabilization in healthy cells. The continuous aggregation of misfolded proteins in the absence of their proper clearance could result in amyloid disease including AD. The neuropathological changes of AD brain include the atypical cellular accumulation of misfolded proteins as well as the loss of neurons and synapses in the cerebral cortex and certain subcortical regions. The mechanism of neurodegeneration in AD that leads to severe neuronal cell death and memory dysfunctions is not completely understood until now. Conclusion: Examining the impact, as well as the consequences of protein misfolding, could help to uncover the molecular etiologies behind the complicated AD pathogenesis.

scholarly journals The amyloid cascade hypothesis and Alzheimer’s disease: A mathematical model

2020 ◽  
pp. 1-20 ◽  
Author(s):  
M. BERTSCH ◽  
B. FRANCHI ◽  
L. MEACCI ◽  
M. PRIMICERIO ◽  
M.C. TESI
Keyword(s):  
Alzheimer’S Disease ◽  
Mathematical Model ◽  
Alzheimer's Disease ◽  
Differential Equations ◽  
Ordinary Differential Equations ◽  
Senile Plaques ◽  
Total Production ◽  
Amyloid Cascade Hypothesis ◽  
Amyloid Cascade ◽  
The Brain

The paper presents a conceptual mathematical model for Alzheimer’s disease (AD). According to the so-called amyloid cascade hypothesis, we assume that the progression of AD is associated with the presence of soluble toxic oligomers of beta-amyloid. Monomers of this protein are produced normally throughout life, but a change in the metabolism may increase their total production and, through aggregation, ultimately results in a large quantity of highly toxic polymers. The evolution from monomeric amyloid produced by the neurons to senile plaques (long and insoluble polymeric amyloid chains) is modelled by a system of ordinary differential equations (ODEs), in the spirit of the Smoluchowski equation. The basic assumptions of the model are that, at the scale of suitably small representative elementary volumes (REVs) of the brain, the production of monomers depends on the average degradation of the neurons and in turn, at a much slower timescale, the degradation is caused by the number of toxic oligomers. To mimic prion-like diffusion of the disease in the brain, we introduce an interaction among adjacent REVs that can be assumed to be isotropic or to follow given preferential patterns. We display the results of numerical simulations which are obtained under some simplifying assumptions. For instance, the amyloid cascade is modelled by just three ordinary differential equations (ODEs), and the simulations refer to abstract 2D domains, simplifications which can be easily avoided at the price of some additional computational costs. Since the model is suitably flexible to incorporate other mechanisms and geometries, we believe that it can be generalised to describe more realistic situations.

scholarly journals The Pathogenesis of Alzheimer's Disease: A Reevaluation of the “Amyloid Cascade Hypothesis”

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
R. A. Armstrong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Senile Plaques ◽  
Amyloid Cascade Hypothesis ◽  
Amyloid A ◽  
Molecular Determinants ◽  
Relationship Of ◽  
The Relationship ◽  
Amyloid Cascade

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 ofβ-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.

Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

2020 ◽  
Vol 26 ◽  
Author(s):  
Nimra Javaid ◽  
Muhammad Ajmal Shah ◽  
Azhar Rasul ◽  
Zunera Chauhdary ◽  
Uzma Saleem ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ellagic Acid ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Acetylcholinesterase Activity ◽  
Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

scholarly journals Fleshing out the amyloid cascade hypothesis: the molecular biology of Alzheimer's disease

2000 ◽  
Vol 2 (2) ◽  
pp. 101-110 ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Biology ◽  
Basic Science ◽  
Amyloid Protein ◽  
Amyloid Cascade Hypothesis ◽  
Protein Tau ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Amyloid Cascade

Alzheimer's disease (AD) is a disorder of two pathologies- plaques and tangles. The former have as a key constituent amyloid protein and the latter the microtubule-associaied protein tau. Genetics has demonstrated that changes in either protein are sufficient to cause dementia. The amyloid cascade hypothesis proposes that plaque-related changes precede tangle-related changes and positions amyloid as central to the degeneration of AD. All the evidence suggests this is correct, including evidence that presenil ins alter the processing of the amyloid precursor protein and evidence that disrupting the normal properties of tau underlies the related froniotemporal dementias. The amyloid cascade hypothesis has provided the basis for nearly a decade of intensive basic science - the skeleton of that hypothesis can now be fleshed out, and confidence is growing that this will result in useful disease-modifying therapies in the future.

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