The amyloid hypothesis is too good to be true

Kurkinen, Markku

doi:10.15761/adcn.1000106

Cited by 10 publications

(9 citation statements)

References 90 publications

(103 reference statements)

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“…In one study, neuronal death was prevented by adding amyloids [ 120 ]. It has been shown that all known developed drugs with an anti-amyloid effect cause death in people [ 121 , 122 ]. For example, active Aβ1–42 immunization (with AN-1792) resulted in 6% of patients developing meningoencephalitis [ 123 ].…”

Section: Anti-amyloid Therapy and Its Problemsmentioning

confidence: 99%

Amyloids: The History of Toxicity and Functionality

Yakupova

Bobyleva

Shumeyko

et al. 2021

Biology

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Proteins can perform their specific function due to their molecular structure. Partial or complete unfolding of the polypeptide chain may lead to the misfolding and aggregation of proteins in turn, resulting in the formation of different structures such as amyloid aggregates. Amyloids are rigid protein aggregates with the cross-β structure, resistant to most solvents and proteases. Because of their resistance to proteolysis, amyloid aggregates formed in the organism accumulate in tissues, promoting the development of various diseases called amyloidosis, for instance Alzheimer’s diseases (AD). According to the main hypothesis, it is considered that the cause of AD is the formation and accumulation of amyloid plaques of Aβ. That is why Aβ-amyloid is the most studied representative of amyloids. Therefore, in this review, special attention is paid to the history of Aβ-amyloid toxicity. We note the main problems with anti-amyloid therapy and write about new views on amyloids that can play positive roles in the different organisms including humans.

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Section: Anti-amyloid Therapy and Its Problemsmentioning

confidence: 99%

Amyloids: The History of Toxicity and Functionality

Yakupova

Bobyleva

Shumeyko

et al. 2021

Biology

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“…2 Yet, several facts and experimental studies are against the hypothesis. [3][4][5][6][7][8] All AD trials, hundreds of them over the years, whether with β-or γ-secretase inhibitors to reduce Aβ peptides production or with anti-Aβ antibodies to clear amyloid from the brain, have failed to stop or slow the cognitive decline or improve the daily living of AD patients. Similarly, in preventive trials in cognitively unimpaired people at high…”

Section: Trials and Failuresmentioning

confidence: 99%

Alzheimer’s trials: A cul-de-sac with no end in sight

Kurkinen¹

2021

Adv Clin Exp Med

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We don't understand Alzheimer, its origin and disease mechanisms. The absence of disease-modifying treatments for Alzheimer today is due to the amyloid hypothesis, a misguided hypothesis of Alzheimer's disease etiology, which has dominated Alzheimer research, drug development, and clinical trials for 30 years. However, the hypothesis is not dead yet, as exemplified by the recent resurrection of clinical trials with aducanumab. Recent advances in Alzheimer research include astrocytes, synaptic function and glutamate signaling. Many studies indicate EAAT2 as a promising target in drug discovery and clinical development for novel therapies in Alzheimer's disease, and other neurologic and psychiatric diseases.

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“…The amyloid cascade hypothesis [20] and the oligomeric amyloid hypothesis [116] evidently contradict each other [124], thereby lowering the level of a huge body of data obtained via in vitro and in vivo studies. Thus, the question remains open as to the toxicity of amyloids in vivo and the expediency of designing new drugs based on contradictory hypotheses which are associated with a pathogenic factor whose toxicity has not yet been proven [22].…”

Section: Aβ Neurotoxicity: Which Peptide Is a Therapeutic Targetmentioning

confidence: 99%

“…The genesis of degenerative processes and memory impairment before the appearance of amyloids in the brain, and the premature death of transgenic animals preclude using these animals as adequate models of sporadic AD [126]. This view is supported by a large body of clinical trials showing negative effects, and even death in sporadic AD patients who received anti-amyloid preparations [22,[138][139][140], despite their therapeutic effect having been confirmed in transgenic mice [141][142][143]. It is clear that any animal model has its advantages and disadvantages, but patients' lives depend on a model that meets the main requirement of equivalent action in animal models and patients and development of safety drugs.…”

Section: Can Transgenic Rodents Be Used As a Suitable Model For Sporamentioning

confidence: 99%

“…The "amyloid cascade hypothesis" [20] has greatly influenced research over the last twenty years with considerable effort devoted to designing new anti-amyloid drugs, and although there is still no cure for AD [21,22], this hypothesis remains the most prevalent. Nevertheless, the key points of the hypothesis suggesting a central role for amyloid plaques in disease development and considering the brain and its age-related changes independently of the blood flow are paradoxical rather than convincing.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Erythrocytic Hypothesis of Brain Energy Crisis in Sporadic Alzheimer Disease: Possible Consequences and Supporting Evidence

Kosenko

Tikhonova

Alilova

et al. 2020

JCM

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Alzheimer’s disease (AD) is a fatal form of dementia of unknown etiology. Although amyloid plaque accumulation in the brain has been the subject of intensive research in disease pathogenesis and anti-amyloid drug development; the continued failures of the clinical trials suggest that amyloids are not a key cause of AD and new approaches to AD investigation and treatment are needed. We propose a new hypothesis of AD development based on metabolic abnormalities in circulating red blood cells (RBCs) that slow down oxygen release from RBCs into brain tissue which in turn leads to hypoxia-induced brain energy crisis; loss of neurons; and progressive atrophy preceding cognitive dysfunction. This review summarizes current evidence for the erythrocytic hypothesis of AD development and provides new insights into the causes of neurodegeneration offering an innovative way to diagnose and treat this systemic disease.

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The amyloid hypothesis is too good to be true

Cited by 10 publications

References 90 publications

Amyloids: The History of Toxicity and Functionality

Amyloids: The History of Toxicity and Functionality

Alzheimer’s trials: A cul-de-sac with no end in sight

The Erythrocytic Hypothesis of Brain Energy Crisis in Sporadic Alzheimer Disease: Possible Consequences and Supporting Evidence

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