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Inhibition of BACE1 for benefiting Alzheimer's patients

Award Number: RF1AG046929
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2013
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Inhibition of BACE1 for benefiting Alzheimer's patients - ABSTRACT Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by the presence of amyloid plaques and neurofibrillary tangles. Although it remains highly contested, the “Amyloid Cascade Hypothesis” is still gaining support from both human and mouse studies that suggest an imbalance between the production and clearance of Aβ as an early or often initiating factor in AD pathogenesis. For AD therapy, decreasing Aβ generation or enhancing Aβ clearance is being actively pursued. Aβ is generated from amyloid precursor protein (APP) through two sequential proteolytic cleavages by BACE1 and γ-secretase. Inhibition of BACE1 is expected to block the formation of Aβ, thereby reducing amyloid deposition in AD patients. Five BACE1 inhibitors are currently in Phase II/III clinical trials thanks to breakthrough progress in developing central nervous system (CNS)-penetrable BACE1 inhibitors. While results from these trials are eagerly anticipated, one such trial was surprisingly terminated in early 2017. This setback will no doubt raise questions as to whether BACE1 inhibitors should still proceed in clinical trials. While pharmaceutical companies are testing these compounds in humans, we aims to answer the question as to whether controlled inhibition of BACE1 activity in the adult will have ultimate effects on reducing or reversing AD pathologies by using BACE1 conditional knockout (KO) mice. We found that deletion of BACE1 in 5xFAD mice at early adult stages is sufficient to remove pre-existing amyloid plaques. However, many important questions remain to be answered. For example, it is not understood as to how pre-existing plaques can be removed and how BACE1 inhibition plays a role in removing these existing amyloid plaques. It is also not yet clear as to whether significant inhibition or deletion of BACE1 at later adult stages will have similar effects on removing existing amyloid plaques, and this question is most relevant to BACE1 inhibitory drugs that are likely to be given to elderly patients. In this study, we aim to test our hypothesis that BACE1 inhibition will not only reduce generation of β-amyloid peptides, but will also enhance clearance of β-amyloid peptides. Our two specific aims are: 1) To determine whether deletion of BACE1 in older adult mice reverses pre-formed amyloid plaques in AD transgenic mouse brains; and 2) To investigate how pre-formed amyloid plaques are removed after BACE1 deletion. We postulate that BACE1 inhibition enhances phagocytic functions in microglia by efficiently removing amyloid plaques, and we have obtained preliminary results to support this hypothesis.


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: 2023 ( Subtotal = $0 )
2023	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	6	10/21/2022	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	6	12/9/2019	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $170,306 )
2019	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	6	7/16/2019	COMPETING CONTINUATION	$170,306
														Subtotal = $170,306

Issue Date FY: 2018 ( Subtotal = $3,255,415 )
2018	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	6	8/22/2018	COMPETING CONTINUATION	$646,409
2018	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	001	6	9/20/2018	COMPETING CONTINUATION	$2,609,006
														Subtotal = $3,255,415

Grand Total All Awards = $3,425,721

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Inhibition of BACE1 for benefiting Alzheimer's patients

Award Number: RF1AG046929

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2013

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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