Switching On/Off Amyloid Plaque Formation in Transgenic Animal Models of Alzheimer’s Disease

Abstract

A hallmark of Alzheimer’s disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aβ) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aβ may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis, any agent that has the capability to inhibit Aβ aggregation and/or destroy amyloid plaques represents a potential disease-modifying drug. In 2023, a humanized IgG1 monoclonal antibody (lecanemab) against the Aβ-soluble protofibrils was approved by the US FDA for AD therapy, thus providing compelling support to the amyloid hypothesis. To acquire a deeper insight on the in vivo Aβ aggregation, various animal models, including aged herbivores and carnivores, non-human primates, transgenic rodents, fish and worms were widely exploited. This review is based on the recent data obtained using transgenic animal AD models and presents experimental verification of the critical role in Aβ aggregation seeding of the interactions between zinc ions, Aβ with the isomerized Asp7 (isoD7-Aβ) and the α4β2 nicotinic acetylcholine receptor.

Age, sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients

“…To characterize the initiation and progression of Alzheimer’s-related neuropathology, longitudinal immunohistochemistry analyses were run on sagittally-cut brain hemispheres in female and male 6-, 12-, 15-, 18-, and 21-month-old (oldest age dependent upon survival) ( n = 3–8 mice of each sex per age group) 3xTg-AD mice. Wild-type mice do not naturally develop Aβ plaques and NFTs [ 43 – 45 ], therefore B6129 mice were not included in these analyses. Characteristic hallmarks of Alzheimer’s neuropathology, Aβ plaques, NFTs, and total tau expression were analyzed.…”

“…To validate our transcriptomic findings’ relevance and translational impact in 3xTg-AD mice, we sought to determine how and if the observed sex-specific molecular profiles in our animal model compared to Alzheimer’s disease-related changes in human brains. We examined DEGs in the parahippocampal gyrus (PHG) of males ( n = 52) and females ( n = 103) with Alzheimer’s disease compared to sex and age-matched (60–90 + years-old) non-demented controls ( n = 32 males, n = 39 females), obtained from the Mount Sinai Brain Bank (MSBB) study [ 43 ]. The PHG has been shown to carry the strongest molecular signal of late-onset Alzheimer’s disease [ 50 ].…”