Altered lipid metabolism has been implicated in the pathogenesis of several neurodegenerative diseases. In this project we will test the hypothesis that the accumulation of specific lipid species is involved in vulnerability of different brain regions and is associated to the apolipoprotein E (APOE) genotype. To test this we will use a mouse model of a rare monogenic neurodegenerative disease Niemann-Pick type C (NPC), that shares several similarities with Alzheimer’s disease (AD), and apolipoprotein E3/E4 knock-in mice (ApoE3/E4-KI) that carry the ε3 or ε4 allele of APOE, the main cholesterol transporter in the brain and the major genetic risk factor of AD. In the context of NPC disease, we will test the hypothesis that cerebellum, the most vulnerable brain region in NPC disease, shows a specific lipid profile that drives neurodegenerative disease processes compared to hippocampus which appears to be spared in NPC. In the context of AD we hypothesize that lipid profiles will differ according to the APOE genotype, E4 vs. E3. In addition, we propose that the accumulation of specific lipid species within the endolysosomal pathway causes enlargement of early endosomes – one of the earliest pathological features of both NPC and AD.

To test this we will perform the following specific aims: Specific aim 1. To characterise lipid profiles of the cerebellum and hippocampus between wt, NPC disease and ApoE3/4 mouse brains; Specific aim 2. To analyse the lipid profile of endolysosomal vesicles within the cerebellum and hippocampus of wt and NPC mice as well as in ApoE3/4 mouse brains; Specific aim 3. To characterise altered metabolism of ApoE in NPC and ApoE3/4 mouse brains. These studies may provide new insights into the role of lipids in the pathogenesis of AD and NPC disease, and hopefully open new lipid-targeted approaches for prevention or treatment options against these devastating diseases.

The proposed studies will be conducted through collaboration between Dr. Hecimovic and Dr. Potier, the two female group leaders at the Rudjer Boskovic Institute (RBI) (Zagreb, Croatia) and the Brain and Spine Institute (ICM- Hôpital de la Pitié-Salpêtrière) (Paris, France), respectively. Hecimovic team will benefit by gaining the knowledge and technical skills in the analysis of APOE metabolism and lipid profiling. Potier team will benefit by initiating studies on NPC disease and on endolysosomal fractionation of different brain regions (hippocampus, cerebellum and cortex).