The pathomimetic oAl325-35 model of Alzheimer's disease: Potential for screening of new therapeutic agents

Alzheimer's disease (AD) is the most common form of dementia in the elderly, currently affecting more than 40 million people worldwide. The two main histopathological hallmarks of AD were identified in the 1980s: senile plaques (composed of aggregated amyloid-l3 (Al3) peptides) and neurofibrillary tangles (composed of hyperphosphorylated tau protein). In the human brain, both Al3 and tau show aggregation into soluble and insoluble oligomers. Soluble oligomers of Al3 include their most predominant forms - Al31-40 and Al31-42 - as well as shorter peptides such as Al325-35 or Al325-35/40.Most animal models of AD have been developed using transgenesis, based on identified human mutations. However, these familial forms of AD represent less than 1% of AD cases. In this context, the idea emerged in the 1990s to directly inject the Al325-35 fragment into the rodent brain to develop an acute model of AD that could mimic the disease's sporadic forms (99% of all cases).This review aims to: (1) summarize the biological activity of Al325-35, focusing on its impact on the main structural and functional alterations observed in AD (cognitive deficits, APP misprocessing, tau system dysfunction, neuroinflammation, oxidative stress, cholinergic and glutamatergic alterations, HPA axis dysregulation, synaptic deficits and cell death); and (2) confirm the interest of this pathomimetic model in AD research, as it has helped identify and characterize many molecules (marketed, in clinical development, and in preclinical testing), and to the development of alternative approaches for AD prevention and therapy.Today, the Al325-35 model appears as a first-intent choice model to rapidly screen the symptomatic or neuroprotective potencies of new compounds, chemical series, or innovative therapeutic strategies.(c) 2023 Published by Elsevier Inc.

Automated summary

Alzheimer's disease (AD) is a common form of dementia that affects over 40 million people worldwide. This review focuses on the biological activity of the Al325-35 fragment, which plays a role in the main structural and functional alterations observed in AD. The Al325-35 model is a valuable tool for screening new compounds and developing alternative approaches for AD prevention and therapy.