Are mechanisms leading to FAD, SAD and age-associated cognitive decline similar?

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 Aβ peptides. These peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-­terminal fragment, β-­CTF, which is then processed into several Aβ isoforms by γ-­secretase. Genetic data suggest that regulation of APP processing contributes to AD. In addition, a polymorfism 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 and the mechanisms by which the protective mutation protects humans from AD and normal aging-­dependent cognitive decline, we introduced a familial APP mutation (the Swedish K670N/M671L mutation, Apps rats), the protective APP mutation (Appp 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 Aβ region: given that aggregated forms of Aβ are considered by most the main pathogenic factor in AD, and given that human Aβ may have higher propensity than rodent Aβ to form yet-­to-­be-­identified toxic forms of Aβ, together with the Swedish mutations we introduced mutations to “humanize” the rat Aβ sequence. As controls, we produced rats carrying only the humanized Aβ 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 Aβ and can readily deposit amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic Abβ have a central pathogenic role. We propose to dissect protective mechanisms triggered by the rare protective APP variant using these KI rat models. We will study the impact of Appp on the pathological processes triggered by the Apps and Psen1LF FAD mutations and on normal aging-­ dependent cognitive decline. We will analyze APP processing, brain pathology, neuro-­ inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory. Dissecting protective pathways set off by the Appp variant may pave the way to therapeutic approaches that can prevent dementia as well as “normal” cognitive decline mimicking the mechanisms triggered by the protective APP variant.