Cholinergic neurodegeneration and cholesterol metabolism dysregulation by constitutive p75NTR signaling in the p75exonIII-KO mice

16 páginas, 7 figurasDegeneration of basal forebrain cholinergic neurons (BFCNs) is a hallmark of Alzheimer's disease (AD). However, few mouse models of AD recapitulate the neurodegeneration of the cholinergic system. The p75 neurotrophin receptor, p75NTR, has been associated with the degeneration of BFCNs in AD. The senescence-accelerated mouse prone number 8 (SAMP8) is a well-accepted model of accelerated and pathological aging. To gain a better understanding of the role of p75NTR in the basal forebrain during aging, we generated a new mouse line, the SAMP8-p75exonIII-/-. Deletion of p75NTR in the SAMP8 background induces an increase in the number of BFCNs at birth, followed by a rapid decline during aging compared to the C57/BL6 background. This decrease in the number of BFCNs correlates with a worsening in the Y-maze memory test at 6 months in the SAMP8-p75exonIII-/-. We found that SAMP8-p75exonIII-/- and C57/BL6-p75exonIII-/- mice expressed constitutively a short isoform of p75NTR that correlates with an upregulation of the protein levels of SREBP2 and its targets, HMGCR and LDLR, in the BF of both SAMP8-p75exonIII-/- and C57/BL6-p75exonIII-/- mice. As the neurodegeneration of the cholinergic system and the dysregulation of cholesterol metabolism are implicated in AD, we postulate that the generated SAMP8-p75exonIII-/- mouse strain might constitute a good model to study long-term cholinergic neurodegeneration in the CNS. In addition, our results support the role of p75NTR signaling in cholesterol biosynthesis regulation.MV acknowledges the Spanish Ministry of Science and Innovation (grants SAG2017/84096-R and PID2021-127600NB-I00) and the European Commission–NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). AB-M has a INVESTIGO contract from the Generalitat Valenciana (INVEST/2022/456). MV and HM to Generalitat Valenciana (PROMETEO 2018/055 and AICO23 CIAICO/2022/074) and HM to Spanish Ministry of Science and Innovation (grant PID2019-111225RB-I00).Peer reviewe