Immune Injury of the Central Nervous System in Aged Humanized Transgenic apolipoprotein E Isoform-specific Knockin Mice

• Applicant: Changjun Yin, Ph.D.
• Subject Area: Cardiology, Angiology ; Immunology ; Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280398872

Alzheimer disease (AD) and vascular dementia (VD) are the leading causes for dementia. Both forms of dementia share the same risk factors such as aging, hyperlipidemia, atherosclerosis, and the apolipoprotein E4 (Apoe4) genotype. However, relations of hyperlipidemia, atherosclerosis, apolipoprotein E genotype, and alterations in brain function during aging are not clear. A better understanding of the mechanisms how hyperlipidemia and apolipoprotein E (Apoe) isoforms affect the central nervous system (CNS) will be important to define molecular mechanisms of VD. Our unpublished data reveal hitherto unrecognized mechanisms of immune injury in aged Apoe-/- mouse brains: These include lipid accumulation in distinct hotspots of the brain parenchyma and the choroid plexus (CP), i.e. the structure that produces cerebrospinal fluid; formation of macrophage/microglia infiltrates in brain parenchyma; glia cell activation; activation of the complement pathway in CP and brain parenchyma; neuronal axon loss due to phagocytosis by macrophages; blood brain barrier (BBB) breakdown; and T/B plasma cell aggregates in the meninges and brain parenchyma. However, whether these changes are a direct result of hyperlipidemia or due to the absence of Apoe has not been determined. One way to address these fundamental issues is the use of humanized transgenic Apoe isoform-specific knockin mice. We hypothesize that hyperlipidemia may induce immune-mediated brain injury before impairment of cerebral blood flow causes strokes. We plan to (Aim1) define roles of hyperlipidemia and of apolipoprotein E isoforms in causing brain injury by using aged humanized Apoe4 knockin (KI) and Apoe3 KI mice; to (Aim2) analyze the effects of a complement inhibitor C5 RNAi (liver-specific) in aged Apoe-/- mice; and to construct (Aim3) microarray-based transcript atlases together with FACS analyses of aged Apoe-/- mouse brains, and in vitro biochemical apolipoprotein isoform binding and inhibition studies, and (Aim4) detection of lipid and inflammatory cell infiltration in the choroid plexus in aged hyperlipidemic dementia patients (non-stroke patients).

• DFG Programme: Research Grants