Wednesday, May 1, 2024
5/1/2024
Project Summary/Abstract Alzheimer's Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aß peptides. These peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-terminal fragment, ß-CTF, which is then processed into several Aß isoforms by ¿-secretase. Genetic data suggest that regulation of APP processing contributes to AD. In addition, a polymorphism of APP that reduces processing of APP by BACE1 protects from sporadic AD and from normal aging-dependent cognitive decline. Thus, the human genetic evidence indicates that APP and APP processing are important for normal cognitive functions. To gain insights into the pathogenic mechanisms of AD we introduced a familial APP mutation (the Swedish K670N/M671L mutation, AppS rats) and a familial PSEN1 mutation (L435F, Psen1LF rats) into the genomic App and Psen1 rat loci, respectively. Rat and human APP differ by 3 amino-acids in the Aß region: given that aggregated forms of Aß are considered by most the main pathogenic factor in AD, and given that human Aß may have higher propensity than rodent Aß to form yet-to-be-identified toxic forms of Aß, together with the Swedish mutations we introduced mutations to “humanize” the rat Aß sequence. As controls, we produced rats carrying only the humanized Aß sequence (Apph rats). We choose a knock in (KI) approach rather than the more common transgenic overexpression approach because KI models make no preconceived assumption about pathogenic mechanisms, except the unbiased genetic one. In contrast, transgenic models, which produce high levels of Aß and can readily deposit amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic Aß have a central pathogenic role. We propose to dissect pathogenic mechanisms of neurodegeneration using these KI rat models of FAD. We will study the impact of App and Psen1 FAD mutations on APP processing, brain pathology, neuro-inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory. In addition, we will assess the role of distinct APP-derived metabolites in neurodegenerative processes triggered by mutant APP and PSEN1. These studies will test the mainstream hypotheses but also consider alterative pathogenic mechanisms, including the possibility that FAD pathogenesis may depend on the alteration of the normal function of APP and PSEN1 in the brain.
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