Backgroundγ‐Secretase is an intramembrane protease which plays a pivotal role in the onset and progression of Alzheimer’s disease (AD). Presenilin provides the catalytic activity of which two homologues exist, Presenilin‐1 and Presenilin‐2 (Psen1/2). Psen2/γ‐secretase complexes are restricted in their localization to the late endosomes and lysosomes, as opposed to the broader distribution of PSEN1/ γ‐secretase, making it the main generator of intracellular abeta (Aβ). Although the focus has been on the extracellular pool, this toxic intracellular pool has been shown to precede plaque and tangle formation and correlates well with synaptic dysfunction highlighting its importance. This project aims to unravel the effects of altered Psen2 expression and this intracellular pool on AD pathogenesis.MethodsWe generated novel mouse models by crossing the well characterized APP NL‐G‐F model with a Psen2 knock out (KO) mouse and an in‐house generated Psen2 knock in (KI) model carrying the familial AD‐linked N141I mutation (FAD‐Psen2).ResultsCuriously, opposed to expectations, we found an identical accelerated plaque pathology coinciding with the presence of dystrophic neurites and amyloid precursor protein c‐terminal fragment (APP‐CTF) accumulation in both genotypes. These alterations in pathology equally translated to an earlier deficit in working memory for both APPxPsen2KO and APPxFADPsen2. In contrast, gliosis was markedly different with increased and earlier microglia recruitment in the case of APPxPsen2KO whereas APPxFAD‐Psen2 displayed a delayed recruitment.ConclusionThese surprising differential effects on distinct pathological features suggest both a protective role for Psen2 as well as specific, yet unexplored, roles in neurons as well as glial cells. We are currently examining primary neurons and microglia from the different genotypes to explore underlying molecular mechanisms.
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