Title: Mechanisms of Alzheimer’s disease in the context of Down syndrome
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added from 2020. There are an estimated 6 million people with Down syndrome (DS) worldwide and in developed countries the vast majority of these individuals will develop Alzheimer’s disease neuropathology and dementia (AD-DS), causing their early death. AD-DS has much in common with Alzheimer’s disease (AD) in the general population but historically is under studied because of its complexity. DS is caused by trisomy of chromosome 21 (T21). Thus an additional copy of a gene(s) on chromosome 21 must cause early onset dementia. Indeed, triplication of the chromosome 21 gene APP is sufficient and necessary for early onset AD (EOAD). However, relatively little is known about how the triplication of other chromosome 21 genes effects neurodegeneration in people who have DS. My programme aims to identify the key chromosome 21 genes that modulate neurodegenerative processes, using preclinical models (mouse, fly and human cells) and human post-mortem studies, in order to inform the delivery and development of effective novel treatments for AD-DS. In the next 5-years I propose to tackle two research questions. 1) What gene(s) on chromosome 21 alter the accumulation of amyloid-β in AD-DS? 2) How do trisomy 21-associated immune system differences affect neuroinflammation in AD-DS, and which genes cause these differences? We have shown, in AD-DS animal models, that trisomy of a gene(s) on chromosome 21 other than APP modulates Aβ aggregation. We will determine if this effect is generalizable and identify likely causal regions and genes using alternative preclinical models (mouse and fly) (with Dr. Niccoli, UCL). We will then test the role of the gene(s) identified in AD-DS mouse models, by crossing with gene-knockouts and using gene-knock-down (AAV-mediated RNAi), to normalise gene dose. Dosage sensitivity of candidates and association with Aβ plaque load will be confirmed in human post-mortem brain (AD-DS, age-, Braak-stage and sex-matched EOAD and healthy aging); thereby identifying the novel mechanism causing elevated plaques in people who have AD-DS. People who have DS have an increased risk of infectious and autoimmune disease, and microglia in adults with AD-DS have a different activation profile compared with AD in the general population. We aim to determine the dosage sensitive genes on chromosome 21 that cause these differences and how these alterations effect the development of dementia in people who have DS (with Professor Strydom, KCL). We have identified a region of chromosome 21 that modulates microglia number in mice. We will identify genes in this region that are dosage sensitive in microglia and have altered expression in response to amyloid-β and go on to test the role of these genes in the microglial response to amyloid-β pathology.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS;NEUROLOGICAL