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Hyman, Bradley T

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Neurologic Alterations in Alzheimer's Disease

Hyman, Bradley T

1 August 1989 - 31 August 2011
NATIONAL INSTITUTE ON AGING
Total Funding: $ 7,608,351

FY 2010
5R01AG008487-20
$ 542,628
FY 2009
5R01AG008487-19
$ 532,149
FY 2009
3R01AG008487-18S1
$ 70,276
FY 2008
5R01AG008487-18
$ 516,646
FY 2007
5R01AG008487-17
$ 511,835
FY 2006
2R01AG008487-16
$ 511,768
FY 2005
5R01AG008487-15
$ 562,266
FY 2004
5R01AG008487-14
$ 547,436
FY 2003
5R01AG008487-13
$ 533,040
FY 2002
5R01AG008487-12
$ 574,062
FY 2002
3R01AG008487-11S1
$ 31,000
FY 2001
2R01AG008487-11
$ 505,492
FY 1999
5R01AG008487-10
$ 524,972
FY 1999
3R01AG008487-10S1
$ 20,000
FY 1998
3R01AG008487-09S1
$ 60,712
FY 1998
5R01AG008487-09
$ 432,729
FY 1997
5R01AG008487-08
$ 419,373
FY 1996
5R01AG008487-07
$ 321,090
FY 1996
3R01AG008487-07S1
$ 46,170
FY 1995
2R01AG008487-06
$ 344,707
 
 
$ 7,608,351
Abstract

[unreadable] Neuroanatomical alterations in Alzheimer disease. Alzheimer disease (AD) dementia affects 1 in 10 American families, and costs more than 90 billion dollars a year. Genetic and neuropathological evidence highlight a pathogenic role for Abeta, but the exact mechanism of how Abeta alters neural system function is uncertain. Nonetheless, Abeta is a key therapeutic target, and clinical trials using anti-Abeta approaches are underway. In the last 5 years of this grant we developed in vivo multiphoton microscopy techniques to image Abeta deposits in living transgenic mouse models, and discovered that anti-Abeta immunotherapy can clear existing plaques. Our goal is to test the hypothesis that Abeta induces synaptic failure, and to examine the consequences in both mice and humans of anti-Abeta immunotherapy. Aim 1 examines hypotheses linking plaques with alterations in axons. Whether axonal dystrophies precede or follow plaque formation will be examined by imaging neuronal processes and plaques in young APP X YFP mice, then re-imaging them at later times. Transport of molecules and organelles near and distant from plaques will be examined in vivo using photoactivatable GFP constructs, introduced by AAV and Lentiviral vectors. Aim 2 builds on the observation that postsynaptic elements, including dendritic spines, are lost near plaques. We will examine whether dendritic spines are less stable near plaques by imaging spine turnover. We will also determine if dendritic segments near plaques are functionally less active using a new genetically encoded reporter of synaptic activation, a 3'-5'UTR CAMKIIalpha/EGFP chimeric molecule. Passive immunization against Abeta, and application of oligomeric Abeta, will be used to test the hypothesis that Abeta is directly responsible for these axonal and dendritic pathologies. The third aim proposes parallel studies of pre and postsynaptic structures in human AD autopsy material, including studies of autopsy tissue from individuals who had participated in the first immunotherapy trial, AN1792. Case reports show that plaque clearance occurs after vaccination. We have now organized a collaborative group of neuropathologists from multiple sites to examine systematically human tissue in which antibody mediated clearance of plaques has occurred. We believe that the questions posed in this application have high clinical relevance, and the severity and prevalence of the disease add urgency to these studies. [unreadable] [unreadable] [unreadable]

153 Resulting Publications

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