Molecular and functional analysis of novel late-onset Alzheimer's disease candidate genes in cellular and Drosophila models for Alzheimer's disease
Zusammenfassung der Projektergebnisse
Preservation of cognitive abilities is one of the major medical challenges of the 21st century. Our current inability to prevent or delay age-related cognitive decline and Alzheimer’s disease (AD), and the expected increase in the prevalence of AD is predicted to give rise to a global AD pandemic, with catastrophic social and economic consequences. Our study delineates a novel pathway for the clearance of brain amyloid that is highly relevant to AD and might have direct therapeutic implications. The laboratory of Dr. Rudolph Tanzi has previously found that mutations in a gene called CD33 are associated with increased risk for developing AD. Here, we show that CD33 confers risk for AD by inhibiting the ability of microglia, the immune cells of the brain, to remove toxic amyloid from the aging human brain. The transmembrane protein CD33 regulates several aspects of innate immunity. Before our study, nothing was known about the function of CD33 in the brain. To understand how CD33 serves as a pathogenic risk factor in AD, we performed extensive pathological studies on human brain samples which revealed a prominent microglial expression for CD33 in the aging brain. Remarkably, the numbers of CD33-positive microglia are markedly increased in AD relative to control brains, and closely correlate with the levels of insoluble amyloid beta (Aβ)42 and the amyloid plaque burden. The CD33 mutation, rs3865444, which confers protection against AD, is associated with significant reductions in CD33 microglial expression and levels of insoluble Aβ42. We also found that primary mouse microglial cells lacking CD33 function displayed a dramatic uptake of exogenously-added Aβ42. Consequently, CD33 overexpression in microglial cells strongly inhibits Aβ42 uptake, a process that requires the sialic acid-binding domain of CD33. Finally, CD33 genetic inactivation leads to a marked reduction in insoluble Aβ42 levels and amyloid plaque burden in a mouse model of AD. Thus, CD33 activity in microglial cells promotes Aβ pathology and CD33 emerges as a novel target for drug development in AD. Our study delineates a novel pathway for the clearance of Aβ in the aging brain and provides the first direct evidence that microglial cells are a critical component of the amyloid hypothesis. An improved understanding of CD33 biology might provide unique therapeutic opportunities in AD. Therapies targeting CD33 have already been developed in acute myeloid leukemia, due to its high membrane expression in myeloid cells. This suggests that the development of a CD33 antibody that is able to cross the blood brain barrier could serve as a promising therapeutic approach in AD. Gene Studies Could Point to New Alzheimer's Treatments– U.S. News and World Report: http://health.usnews.com/health-news/news/articles/2013/04/25/gene-studies-could-point-to-new-alzheimerstreatments Alzheimer’s Advance: Gene Could Help to Clear Brain Plaques Responsible for the Disease –Healthland/Time Magazine Online: http://healthland.time.com/2013/04/26/alzheimers-advance-gene-could-help-to-clear-brain-plaquesresponsible-for-the-disease/ New Strategy to Halt Alzheimer's Progress: Housecleaning the Brain – Medical Daily: http://www.medicaldaily.com/articles/14911/20130425/new-strategy-halt-alzheimers-progress-housecleaningbrain.htm Suppressing protein may stem Alzheimer's disease process – MedicalXpress: http://medicalxpress.com/news/2013- 04-alzheimer-gene-potential-treatment.html Alzheimer's risk gene presents potential treatment target – EurekAlert: http://www.eurekalert.org/pub_releases/2013-04/mgh-arg042313.php
Projektbezogene Publikationen (Auswahl)
- Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 2013, 78(4): 631-643
Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, Hooli B, Choi SH, Hyman BT, Tanzi RE
