“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

Abstract

The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

RTN4B‐mediated suppression of Sirtuin 2 activity ameliorates β‐amyloid pathology and cognitive impairment in Alzheimer's disease mouse model

“…The primary neuropathological signs of AD, including the extracellular deposition of amyloid‐β (Aβ) peptides and intracellular neurofibrillary tau tangles, are closely associated with synapse and neuron loss, ultimately memory impairment in AD (De Strooper & Karran, 2016; Palop & Mucke, 2016; Zott, Busche, Sperling, & Konnerth, 2018). Although Aβ theory has been challenged due to the setback of clinical experiments with Aβ as the target, a great many convincing pieces of evidence support that Aβ is the most critical target of AD, and its pathogenesis in AD still acquired a greater depth of understanding (Rao, Asch, Carr, & Yamada, 2020).…”

SkQ1 Suppresses the p38 MAPK Signaling Pathway Involved in Alzheimer’s Disease-Like Pathology in OXYS Rats

“…Existing targets of AD drug research and development include amyloid beta (Aβ), Aβ metabolism/catabolism, tau protein, inflammation, cholesterol, the cholinergic system, and other neurotransmitter systems. Nonetheless, none of them has been validated as a therapeutically effective target [1]. The hallmark of AD is defective proteostasis, namely, aggregation and accumulation of Aβ and hyperphosphorylated tau protein in neurofibrillary tangles in the brain [2,3], in combination with oxidative stress and mitochondrial dysfunction.…”

Graphene oxide improves postoperative cognitive dysfunction by maximally alleviating amyloid beta burden in mice

“…After cleavage, β-CTF generates Aβ peptides, most of which are 40 (Aβ40) or 42 (Aβ42) residues in length. Aβ42 is more hydrophobic and more prone to fibril formation than Aβ40, and it is also the predominant isoform found in cerebral plaques 37 . Both soluble and insoluble forms of Aβ have been found in cells 33 , 38 , and we detected the total content of Aβ42 and Aβ40.…”