Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease

Kepp, Kasper Planeta

doi:10.3233/jad-160550

Cited by 76 publications

(82 citation statements)

References 149 publications

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“…High levels of AICD may also play an important role in the pathology in human brains [236] . The challenges to the Amyloid Hypothesis of Alzheimer's Disease are sharply formulated [237] . There are several other competing hypotheses, such as the cholinergic hypothesis, the tau hypothesis, and the hypothesis that some other environmental risk factors, may contribute additional causes of the disease.…”

Section: Non-aβ Hypothesismentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

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Section: Non-aβ Hypothesismentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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“…Several anti‐Aβ monoclonal antibody therapies (Doody et al, ; Vandenberghe et al, ) and a selection of β‐secretase (BACE1) inhibitors (Vassar, ) have progressed as far as phase III clinical trials but have failed to translate into commercial medicines. These recent high‐profile failures have led some to believe that new hypotheses of AD are required, as the current understanding has provided no progress to a medicine (Kepp, ). This has led researchers to inspect features of the brain other than the neural cells, such as the extracellular matrix (ECM), for novel inspiration.…”

Section: Introductionmentioning

confidence: 99%

The potential of memory enhancement through modulation of perineuronal nets

Duncan

Foster

Kwok

2019

British J Pharmacology

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With an increasingly aging global population, the incidence of neurological diseases such as dementia is set to increase to unmanageable levels, yet there are currently only symptomatic therapies available for treatment. The mechanisms underlying the development of some forms of dementia, such as Alzheimer's disease (AD), are not yet completely elucidated with several competing hypotheses existing. During the closure of the critical period in the brain, significant compositional changes occur to the neural extracellular matrix (ECM). Specifically, condensed mesh‐like structures called perineuronal nets (PNNs) form around subsets of neurons and have a profound effect on axonal growth and limit neuronal plasticity. These PNNs act as a morphological checkpoint and can influence memory and cognition. Manipulating these important ECM structures may provide the key to reactivating plasticity and restoring memory, both of which are severely impaired in AD and other associated neurological diseases. This review explores the current understanding of how PNNs are manipulated and examines potential new methods for PNN modulation. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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“…Whereas aggregation is cytotoxic and potentially related to disease [14][15][16][17], the cellular pathogenic mechanism is unknown and not yet understood [10,14,[18][19][20][21][22][23]. Efforts to identify and target the supposed malicious protein aggregates and oligomers, while possible with inhibitors or antibodies, have so far met with clinical failure [24][25][26][27][28][29]. This begs the question whether we miss a key determinant of disease course, and it is widely debated whether the protein aggregates in any particular shape and size are the root cause of disease or merely a side effect or contributing feature [10,[28][29][30].…”

Section: Introductionmentioning

confidence: 99%

“…They interact with many other molecules and cell parts, preventing the identification of a single pathogenic mode of in vivo action [27,37]. Efforts to reduce the production of the misfolding proteins by inhibitors or reduce oligomer activity by antibodies, which work in simpler tests, have failed to benefit the human patient [26,28,29,38].…”

Section: Introductionmentioning

confidence: 99%

A quantitative model of human neurodegenerative diseases involving protein aggregation

Kepp

2019

Preprint

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Human neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis involve protein aggregation and share many other similarities. It is widely assumed that the protein aggregates exhibit a specific molecular mode of toxic action. This paper presents a simple mathematical model arguing that clinical cognitive status relates to the energy available after subtracting cell maintenance due to general turnover of the misfolded proteins, rather than a specific toxic molecular action per se. Proteomic cost minimization can explain why highly expressed proteins changed less during evolution, leaving more energy for reproducing microorganisms on longer evolutionary timescales. In higher organisms, the excess energy instead defines cognitive capability, and the same equations remarkably apply. Proteomic cost minimization can explain why late-onset neurodegenerative diseases involve protein aggregation. The model rationalizes clinical ages of symptom onset for patients carrying pathogenic protein mutations: Unstable or aggregation-prone mutations confer a direct energy cost of turnover, but other risk modifiers also change the available cellular energy as ultimately defining clinical outcome. Proteomic cost minimization is consistent with current views on biomarker histories, explains conflicting data on overexpression models, and is supported by specific experiments showing that proteasome activity is required to confer toxicity to pathogenic mutants. The mechanism and model lend promise to a quantitative personalized medicine of neurodegenerative disease.

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Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease

Cited by 76 publications

References 149 publications

Amyloid beta: structure, biology and structure-based therapeutic development

Amyloid beta: structure, biology and structure-based therapeutic development

The potential of memory enhancement through modulation of perineuronal nets

A quantitative model of human neurodegenerative diseases involving protein aggregation

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