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A., 1992, Alzheimers-disease — the amyloid cascade hypothesis.

(2005) The Aluminium-Amyloid Cascade Hypothesis and Alzheimer’s Disease.

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The Amyloid Cascade Hypothesis of Alzheimer's Disease?

Investigators have observed genetic defects in individuals with the familial forms of the disease. The genes implicated are the amyloid precursor protein (APP), and the secretases, presenilin 1 and presenilin 2, enzymes involved with APP processing. Mutant forms of these genes induce an overproduction of beta amyloid due to an alteration in APP processing, creating an imbalance between production and clearance, and the clinical and histopathological phenotype associated with AD. This correlation between beta amyloid and the various histological and clinical hallmarks of the disease is the basis for the Amyloid hypothesis as a model for the familial forms of AD. The model, first proposed by Glenner and Wong (), contends that the neurodegenerative disease is due to an imbalance between the generation and clearance of beta amyloid.

Alzheimer's disease: the amyloid cascade hypothesis | Science

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.

Alzheimer's Disease and the Amyloid Cascade Hypothesis…

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Indeed, biochemical and epidemiological studies now indicate that age is the dominant risk factor in sporadic forms of AD. These investigations suggest that the amyloid plaques that are considered the biochemical hallmarks of the disease are also consistent with an age-related misfolding of the APP protein (Chiti and Dobson, ). However, in spite of these studies, proponents of the amyloid hypothesis have maintained that a mutation induced overproduction of beta amyloid underlies both the early onset and the late onset forms of AD, and consequently, both forms of the disease can be ascribed similar etiologies (Hardy, ; Selkoe, ).

Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

The amyloid hypothesis of Alzheimer's disease: …

The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics

In order to be able to test some of the predictions made based on the Inverse Warburg hypothesis, it would be quite useful to have access to an appropriate animal model. Since an enhanced OxPhos activity would be not only a hallmark but also a causative factor of the process leading to neurodegeneration in the context of Alzheimer's disease, development of a mouse model exhibiting such a feature would be useful. The peroxisome proliferator-activated receptor γ coactivator PGC-1α is a key component involved in the regulation of mitochondrial biogenesis. Enhancing mitochondrial biogenesis via an overexpression of PGC-1α might be a good strategy to obtain an enhanced OxPhos activity in the central nervous system and particularly in neurons. Of note, a transgenic mouse overexpressing PGC-1α in all tissues has already been generated (Liang et al., ). Interestingly, when such mice were crossed with the Tg 19959 transgenic mouse model for Alzheimer's disease, it worsened the phenotype by causing mitochondrial abnormalities, exarcerbating amyloid and tau accumulation, inducing neuronal death as well as provoking behavioral abnormalities (as expected according to the Inverse Warburg hypothesis) instead of improving it by enhancing OxPhos activity (as postulated based on the hypothesis that β-amyloid reduces OxPhos activity) (Dumont et al., ). Such trangenic mice aiming at selectively enhancing OxPhos activity in neurons could represent excellent models to test experimentally the validity and usefulness of the Inverse Warburg hypothesis, especially if examined in the context of aging.

According to the Amyloid cascade hypothesis, neuronal loss is due to the toxicity of beta amyloid. However, since beta-amyloid derives from processing of the APP gene, which will be the same in each cell type under the amyloid cascade model, the vulnerability of each neuronal type should be essentially random and non-selective. This prediction of the amyloid hypothesis, however, is inconsistent with the selective neuronal vulnerability.

The amyloid hypothesis for Alzheimer’s disease: a …
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  • The Amyloid Hypothesis of Alzheimer's Disease: …

    The amyloid hypothesis has been the basis for most work on the pathogenesis of Alzheimer’s disease

  • Amyloid Cascade Hypothesis In Alzheimer's Disease

    20/12/2017 · The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the ..

  • Alzheimer’s disease the amyloid cascade hypothesis presentation 1

    Experimental treatments for Alzheimer’s disease put the amyloid cascade hypothesis to the test.

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Alzheimer’s Disease: The Amyloid Cascade Hypothesis J

A new review of processes underlying by Dr. Karl Herrup presents a new synthesis and framework to view this debilitating illness. The current standard view of the cause of is known as the Amyloid Cascade Hypothesis. The existence of plaques in the brains of patients lead to the idea that the plaques may be the cause of the disease (see my earlier blog post ““).

Alzheimer's disease: the amyloid cascade hypothesis,

The amyloid cascade hypothesis and the energetic selection model are two conceptual frameworks that have been invoked to explain the origin of sporadic forms of AD (Hardy and Selkoe, ; Hardy, ; Demetrius and Simon, ; Demetrius and Driver, ). Both models acknowledge the epidemiological fact that age is a primary risk factor for the disease. However, the effect of age on the dynamics of neurodegeneration is analyzed in quite distinct ways.

Alzheimer's disease: the amyloid hypothesis and the ..

The amyloid cascade hypothesis is based on a neuron-centric characterization of the origin and development of the disease. The model essentially does not take into account the interaction between neurons and astrocytes in disease progression. The beta amyloid moieties, the presumed biochemical hallmarks of neurodegeneration, are assumed to be generated by abnormal processing of APP. Age in the context of this model is considered uniquely in terms of its influence on the toxicity of the peptide beta amyloid. In this model, age reflects the time it takes beta amyloid to attain concentrations which are sufficient to impair neuronal function. Accordingly, the sporadic form of the disease can be considered to be determined primarily by the net production rate of beta amyloid. Since this biochemical abnormality is assumed to be determined by aberrant processing of APP, the early onset and sporadic forms of the disease can be ascribed the same etiology. The sporadic form of AD is thus a consequence of genomic instability, primarily the result of mutations in the nuclear genome, and hence can be considered to be a genetic disease. The sequence of pathogenic events leading to AD, in accordance with the amyloid cascade hypothesis is shown in Figure .

the β-amyloid cascade hypothesis of Alzheimer's ..

The peptide beta amyloid is constantly produced in the brain of young and old people. Extracellular beta amyloid levels rise during the day and fall at night (Huang et al., ). In the healthy brain, beta amyloid production and clearance is tightly regulated. In the unhealthy brain, the production and clearance is dysregulated. These considerations are of critical importance in both the amyloid hypothesis and the neuroenergetic model. However, the role which beta amyloid plays in the depictions of sporadic forms of AD are quite distinct and derive from different assumptions regarding the origin and the progression of the disease.

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