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Inhibition of BACE1 for benefiting Alzheimer's patients

Award Number: R01AG046929
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: 06/30/2029

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Inhibition of BACE1 for benefiting Alzheimer's patients - Abstract BACE1 is an enzyme required for Aβ generation, and chemical inhibition of BACE1 has been explored for reducing Aβ generation. Five brain-penetrable BACE1 inhibitory dugs were recently tested in human trials. Unfortunately, despite a noted reduction in Aβ plaque loads, these clinical trials were terminated, largely due to neuronal and synaptic toxicity. This setback indicates the importance to known more BACE1 biology and to develop safer BACE1 inhibitors for AD treatment, especially considering the growing evidence from anti- Aβ trials that reducing Aβ plaques early can lead to reduction of other AD pathologies. In this proposal, we aim to test a novel hypothesis that increasing inhibition of BACE1 in glial cells, along with boosting microglial phagocytic functions, will reduce AD pathologies while minimizing synaptic side effects. This hypothesis is supported by our recent observations that Bace1 deletion in microglia facilitates the transition of homeostatic microglia to more phagocytic stage-1 disease-associated microglia (DAM-1). Consistently, deletion of microglial Bace1 in 5xFAD mice reduces amyloid deposition. If Bace1 in astrocytes is deleted, the expression of genes, such as clusterin (Clu), CXCL14 and ApoE, important for removal of amyloid plaques by astrocytes, is increased. These results suggest that BACE1 inhibition in glial cells has a beneficial effect on the clearance of amyloid plaques. However, many questions remain to be answered. For example, it is not clear whether Bace1 deletion will affect tau pathology. We do not yet know how BACE1 inhibition will enhance microglia to remove tau pathology. Considering the known role of chemoattractant molecule CXCL14 in mediating migration of immune cells and reduced levels of CXCL14 in AD brains, we will ask whether the expected elevated levels of CXCL14, in response to the inhibition by BACE1, will promote phagocytic function of microglia. This question will be address by utilizing an inducible transgenic mouse model that has already been generated. In this proposal, we will explore whether deletion of BACE1 in PS19 mouse microglia will reduce tau pathology in Aim 1. In Aim 2, we will ask whether a low dose inhibition of BACE1 in AD triple-transgenic model coupled with deletion of Bace1 in microglia will reduce both amyloid and tau pathologies effectively. In Aim 3, we will investigate whether enhancing expression of CXCL14 will promote microglia migration and phagocytosis. These studies are centered on improving microglia function and the knowledge gained from this study will help to develop a therapeutic approach that will favor BACE1 inhibition in glial cells coupled with molecular boosters of microglia phagocytic function for AD treatment.


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: 2026 ( Subtotal = $777,423 )
2026	2026	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Aging Research	000	9	7/17/2026	NON-COMPETING CONTINUATION	$777,423
														Subtotal = $777,423

Issue Date FY: 2025 ( Subtotal = $761,875 )
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Aging Research	000	8	7/17/2025	NON-COMPETING CONTINUATION	$761,875
														Subtotal = $761,875

Issue Date FY: 2024 ( Subtotal = $777,423 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Aging Research	000	7	8/21/2024	COMPETING CONTINUATION	$777,423
														Subtotal = $777,423

Issue Date FY: 2019 ( Subtotal = -$170,306 )
2019	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	5	7/16/2019	NON-COMPETING CONTINUATION	-$170,306
														Subtotal = -$170,306

Issue Date FY: 2017 ( Subtotal = $324,925 )
2017	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	002	5	7/7/2017	NON-COMPETING CONTINUATION	$324,925
2017	2016	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	001	4	11/14/2016	EXTENSION WITH OR WITHOUT FUNDS	$87,703
2017	2015	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	3	11/14/2016	NON-COMPETING CONTINUATION	-$87,703
														Subtotal = $324,925

Issue Date FY: 2016 ( Subtotal = $324,925 )
2016	2016	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	4	6/27/2016	EXTENSION WITH OR WITHOUT FUNDS	$324,925
														Subtotal = $324,925

Issue Date FY: 2015 ( Subtotal = $315,177 )
2015	2015	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	3	7/16/2015	NON-COMPETING CONTINUATION	$315,177
														Subtotal = $315,177

Issue Date FY: 2014 ( Subtotal = $324,925 )
2014	2014	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	2	6/25/2014	NON-COMPETING CONTINUATION	$324,925
														Subtotal = $324,925

Issue Date FY: 2013 ( Subtotal = $324,925 )
2013	2013	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	1	9/25/2013	NEW	$324,925
														Subtotal = $324,925

Grand Total All Awards = $3,761,292

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Inhibition of BACE1 for benefiting Alzheimer's patients

Award Number: R01AG046929

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: 06/30/2029

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