Dissecting mechanisms of immune actions in Alzheimer’s disease

Project Number A6
Principle Investigator Prof. Dr. med. Frank Heppner
Department of Neuropathology
Charité – Universitätsmedizin Berlin
Charitéplatz 1
10117 Berlin
Tel. +49 (0)30 450 536042
Fax +49 (0)30 450 536940
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Over the last few years it became obvious that neurodegenerative disorders such as Alzheimer’s disease (AD) display an inflammatory component, which appears to influence disease progression. While intense research efforts in this emerging field are aimed at dissecting, whether inflammation pathogenetically is causal or rather an accompanying byproduct, it is common sense that manipulation of the immune system and its respective pathways can be utilized to influence disease progression. Cerebral β-amyloid (Ab), a pathological hallmark of AD, has been known to attract and activate e.g. microglia as local immune cells. Besides reports on the impact of blood-derived macrophages on Aβ plaques, we recently demonstrated within the framework of this SFB TRR43 project that the ablation of CNS-resident microglia in AD mouse models did not influence the overall Ab catabolism or de novo Ab generation, at least when lacking for a limited time of up to 30 days in two mouse models of cerebral amyloidosis. As direct follow up we are aiming within the next funding period to exchange microglia with bone-marrow derived macrophages in AD mice to induce / restore myloid capacity to tackle Ab (Aim 1). A second line of further dissecting the crosstalk and impact of the immune system in AD is based on our recent finding that genetic deficiency of a soluble immune factor (sIF), typically produced by microglia in the setting of AD, results in significantly reduced Ab levels in AD mice. Despite the fact sIF apparently reveals its main Aβ-reducing effect in the radiation-resistant glial compartment of the brain, blocking of sIF by peripheral administration of neutralizing antibodies similarly resulted in the reduction of cerebral β-amyloid suggesting that sIF poses a potential pharmacological target to combat AD. We now aim to further dissect the precise mechanistic underpinnings of sIF-mediated β-amyloid reduction by manipulating sIF-specific and -associated immune pathways as well as define the cellular sources of sIF in vitro and in vivo (Aim 2). Our third subproject (Aim 3) is aimed at continuing our investigations on whether anti-Aβ antibodies during Aβ immunotherapy exert their action outside or within the CNS. Within the first funding period we successfully generated transgenic mice that exclusively produce soluble and membrane bound (AB9μ) or only membrane bound (AB9μ-dS) anti-Ab IgM antibodies, i.e. we have transgenic mice at hand, which due to the genetic manipulation exhibit anti-Ab responses that are restricted to the periphery. Since we are presently crossing AB9μ and AB9μ-dS to APPPS1 AD mice, we will be able to learn, whether anti-Ab antibodies in the context of Ab vaccination exert their action outside or inside the brain - a set of experiments that may have important implications for future Ab vaccination approaches.


Heppner group

© 2017 - SFB TRR 43