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BACE1 regulation and TNFR Type II receptor in Alzheimers disease

Award Number: R01AG025888
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2005
PERIOD OF PERFORMANCE END DATE: 08/31/2015

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BACE1 regulation and TNFR Type II receptor in Alzheimers disease - DESCRIPTION (provided by applicant): Clinically, Alzheimer's disease (AD) is characterized by dementia of insidious onset; pathologically, it is characterized by the presence of numerous neuritic plaques, neurofibrillary tangles, and a progressive Neurodegeneration. There is exceedingly strong evidence that abnormal assemblies of A¿ are neurotoxic and have a key role in AD. Why A¿ is increased and accumulates or induces Neurodegeneration is unclear. However, the mechanisms of plaque formation and neurodegeneration in AD brains are not clear. We recently described (He et al., 2007) that generation of amyloid 2 (A¿), the main component of plaques, is inhibited by TNFRI deletion, which reduces BACE1 levels via the NF-:B pathway. However, we demonstrated in vitro (Shen et al., 1997) that, unlike TNFRI, which is the TNF death receptor, TNFRII, protects neurons. To examine the roles of TNFRII in APP processing, we cross-bred AD transgenic APP23 mice, which express mutant APP and form many A¿ plaques, with TNFRII knockout mice, to generate TNFRII knockout (TNFRII-/-) in APP23 mice (APP23/TNFRII-/-). Our preliminary results demonstrated that APP23/TNFRII-/- mice have more A¿ plaques and increased A¿ levels at 12 months of age. Thus, we propose a central hypothesis that modulation of TNF type II receptor activity can alter BACE1, A¿ production and AD neuropathology via NF-:B-dependent and independent intracellular signaling pathways. We will use the double transgenic mouse model, APP23/TNFRII-/-, to examine whether these mice exhibit earlier AD-like pathology. If so, we will study the mechanisms, such as possible TNFRII mediated BACE1 through new signal transduction pathways by NF-kB dependent and non-NF-kB dependent manner, and how these mechanisms ultimately result in neuroprotection. We believe that successful completion of the experiments will lead to novel therapeutic interventions. The goal of this application is to determine how TNFRII is regulated in neurons and in mouse brains, how it affects the generation of A¿ and its precursors, and whether increased production of TNFRII may be protective and ameliorate Neurodegeneration and AD-like disease in mice. We expect to identify modulators of TNFRII expression and proteins that interact with TNFRII. We also expect to establish that TNFRII is a major modifier of AD pathogenesis and that increasing TNFRII levels reduces disease. If successful, our findings may provide new targets for the treatment of AD and neurodegeneration. PUBLIC HEALTH RELEVANCE: Neuronal and synaptic losses are the most prominent features in the Alzheimer's disease (AD) brain. AD treatments are presently inadequate, so numerous novel therapy ideas deserve rigorous exploration in the academic and pharmaceutical research communities. Inhibition of tumor necrosis factor and its mediated signal transduction pathway is one potential target area, like TNF type II receptor (TNFRII) for AD treatment. We recently have started a promising clinical trial with a drug inhibiting TNF signal pathway on AD patients, which is FDA approved and NIH awarded. Thus, elucidating the regulatory mechanisms for BACE1 could identify new potential therapeutic targets and therefore diminish possible side effects that could arise by directly targeting BACE1.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2014 ( Subtotal = $373,667 )
2014	2014	THE ROSKAMP INSTITUTE INC	2040 WHITFIELD AVENUE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	9	5/20/2014	NON-COMPETING CONTINUATION	$373,667
														Subtotal = $373,667

Issue Date FY: 2013 ( Subtotal = $353,116 )
2013	2013	THE ROSKAMP INSTITUTE INC	2040 WHITFIELD AVENUE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	8	8/26/2013	NON-COMPETING CONTINUATION	$353,116
														Subtotal = $353,116

Issue Date FY: 2012 ( Subtotal = $373,667 )
2012	2012	THE ROSKAMP INSTITUTE INC	2040 WHITFIELD AVENUE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	7	8/21/2012	NON-COMPETING CONTINUATION	$373,667
														Subtotal = $373,667

Issue Date FY: 2011 ( Subtotal = $373,667 )
2011	2011	THE ROSKAMP INSTITUTE INC	2040 WHITFIELD AVENUE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	6	9/20/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$373,667
2011	2010	ROSKAMP FOUNDATION IRRV TR	2040 WHITFIELD AVENUE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	001	5	9/20/2011	COMPETING CONTINUATION	$0
														Subtotal = $373,667

Issue Date FY: 2010 ( Subtotal = $388,750 )
2010	2010	ROSKAMP FOUNDATION IRRV TR	2040 WHITFIELD AVENUE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	002	5	9/27/2010	COMPETING CONTINUATION	$388,750
2010	2009	SUN HEALTH RESEARCH INSTITUTE	POST OFFICE BOX 1278	SUN CITY	AZ	85372	MARICOPA	USA	Aging Research	000	4	9/27/2010	SUPPLEMENT FOR EXPANSION	$0
2010	2009	SUN HEALTH RESEARCH INSTITUTE	POST OFFICE BOX 1278	SUN CITY	AZ	85372	MARICOPA	USA	Aging Research	001	4	9/27/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $388,750

Issue Date FY: 2009 ( Subtotal = $395,882 )
2009	2009	SUN HEALTH RESEARCH INSTITUTE	P.O. BOX 1278	SUN CITY	AZ	85372	MARICOPA	USA	Aging Research	000	4	7/28/2009	NON-COMPETING CONTINUATION	$309,382
2009	2009	SUN HEALTH RESEARCH INSTITUTE	P.O. BOX 1278	SUN CITY	AZ	85372	MARICOPA	USA	Aging Research	001	4	8/17/2009	SUPPLEMENT FOR EXPANSION	$86,500
														Subtotal = $395,882

Issue Date FY: 2008 ( Subtotal = $334,882 )
2008	2008	SUN HEALTH RESEARCH INSTITUTE	POST OFFICE BOX 1278	SUN CITY	AZ	85372	MARICOPA	USA	Aging Research	001	3	7/8/2008	SUPPLEMENT FOR EXPANSION	$25,500
2008	2008	SUN HEALTH RESEARCH INSTITUTE	POST OFFICE BOX 1278	SUN CITY	AZ	85372	MARICOPA	USA	Aging Research	000	3	7/7/2008	NON-COMPETING CONTINUATION	$309,382
														Subtotal = $334,882

Issue Date FY: 2007 ( Subtotal = $315,696 )
2007	2007	SUN HEALTH RESEARCH INSTITUTE	POST OFFICE BOX 1278	SUN CITY	AZ	85372	MARICOPA	USA	Aging Research	000	2	7/18/2007	NON-COMPETING CONTINUATION	$315,696
														Subtotal = $315,696

Issue Date FY: 2006 ( Subtotal = $325,125 )
2006	2006	SUN HEALTH RESEARCH INSTITUTE	POST OFFICE BOX 1278	SUN CITY	AZ	85372	MARICOPA	USA	Aging Research	000	1	8/14/2006	NEW	$325,125
														Subtotal = $325,125

Grand Total All Awards = $3,234,452

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BACE1 regulation and TNFR Type II receptor in Alzheimers disease

Award Number: R01AG025888

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2005

PERIOD OF PERFORMANCE END DATE: 08/31/2015

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