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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    116—Alzheimer's Disease: Neuroinflammation and Immune Mechanisms

    Sunday, November 10, 2013, 8:00 am - 11:30 am

    116.06: Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta

    Location: 33C

    *A. GRICIUC1, A. SERRANO-POZO2, A. R. PARRADO1, A. N. LESINSKI1, C. N. ASSELIN1, K. MULLIN1, B. HOOLI1, S. H. CHOI1, B. T. HYMAN2, R. E. TANZI1;
    1Genet. and Aging Res. Unit, 2Alzheimerís Dis. Res. Lab., Massachusetts Gen. Hosp. and Harvard Med. Sch., Charlestown, MA

    Abstract Body: No therapy is available to prevent, stop or delay Alzheimer’s disease (AD), the most prevalent neurodegenerative disease and the leading cause of dementia among the elderly. We have previously shown that the CD33 gene is a novel risk factor for late-onset AD. The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity. No functions have been described for CD33 in the brain. Here, we describe a novel pathway that links CD33 activity, microglial cell function and amyloid beta pathology in the aging human brain [1]. Extensive histological studies on post-mortem human brain samples revealed that CD33 exhibits a prominent microglial expression in the aging brain. Remarkably, the number of CD33-positive microglia is markedly increased in AD relative to age-matched control brains. The minor (T) allele of the CD33 single nucleotide polymorphism rs3865444, which confers protection against AD, is associated with marked reductions in CD33 protein levels, CD33 microglial expression and levels of insoluble amyloid beta 42 (Aβ42) in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia closely correlate with the levels of insoluble Aβ42 levels and plaque burden in AD brain. To further explore the connection between CD33 activity, microglial cell function and amyloid beta pathology, we derived primary microglial cultures from wild-type and CD33 knockout mice. We found that CD33 inactivation dramatically enhances the microglial uptake of exogenously-added Aβ42. Consequently, CD33 overexpression in BV2 microglial cells strongly inhibits Aβ42 uptake, a process that requires the sialic acid-binding domain of CD33. Finally, CD33 inactivation leads to a marked reduction in insoluble Aβ42 levels and amyloid plaque burden in APP/PS1 transgenic mice. Therefore, CD33 activity in microglial cells promotes amyloid beta pathology and inhibition of CD33 function could represent a novel therapy for AD.
    [1] Griciuc A. et al. Alzheimer's Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta. Neuron, In Press

    Lay Language Summary: Our study delineates a novel pathway for the clearance of brain amyloid that is highly relevant to Alzheimer’s disease (AD) and might have direct therapeutic implications. We have 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.
    Preservation of cognitive abilities is one of the major medical challenges of the 21st century. AD emerges as one of the leading causes of disability worldwide. It is the leading cause of dementia among the elderly and affects more than five million Americans. Currently, no therapy is available to prevent, stop or delay AD. Our findings suggest a novel avenue for the prevention and treatment of AD.
    Before our study, nothing was known about the function of CD33 in the brain. We show for the first time that CD33 is expressed in microglial cells in the aging human brain. Moreover, we uncover a novel function for CD33 in the clearance of brain amyloid, which is highly relevant to AD pathogenesis.
    Massive accumulation of toxic amyloid species in the aging brain is thought to be the major driving force behind the development of cognitive decline and AD dementia. Amyloid species are particularly toxic for synapses, the initial sites of memory formation in the brain. Synaptic dysfunction and loss of synapses are early pathogenic changes in the AD brain and together with the subsequent loss of nerve cells are responsible for the development of cognitive decline and dementia. Our results suggest that the activity of CD33 in microglial cells is critical for the control of amyloid levels in the brain. Individuals with higher levels of CD33 in microglia have increased levels of brain amyloid and are more likely to develop AD. Increased levels of CD33 impair the ability of microglia to clear toxic amyloid, thus potentiating its deleterious effects in the aging brain. Remarkably, inactivation of the CD33 gene in a mouse model of AD led to a marked decrease in amyloid levels and the number of amyloid plaques in the brain.
    Our findings indicate that CD33 inhibits the uptake and clearance of amyloid by microglia. They raise the possibility that pharmacologic inactivation of CD33 activity could be employed therapeutically to prevent, stop or delay AD.
    The molecular mechanisms of AD remain elusive. Although several genes, including CD33, have recently been associated with AD, little is known about their role in AD pathogenesis. Our results indicate that microglial cells are essential for the control of amyloid levels in the aging brain and identify CD33 as a critical regulator of microglial cell function. Understanding the molecular interactions underlying the activity of CD33 in microglial cells might uncover additional cellular targets for drug development in AD.