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Mechanisms of axonal protection by astrocytes and microglia inAlzheimer disease

Award Number: R01AG074657
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Mechanisms of axonal protection by astrocytes and microglia inAlzheimer disease - PROJECT SUMMARY Microglia and astrocytes have long been suspected of participating in the pathogenesis of Alzheimer’s disease (AD). However, it is not clear how these cells orchestrate their reactions in AD and whether they play protective or deleterious roles that can be targeted therapeutically. We recently discovered a potentially neuroprotective function that we termed the “microglia barrier”. We found that the robust encapsulation of Aβ deposits by microglia processes cause Aβ aggregates to become compact, less toxic and insulated from adjacent neurites, thereby reducing the formation of dystrophic axons. This neuroprotective function was severely disrupted in mice lacking Trem2 or Dap12, which have defects in microglia polarization towards plaques, leading to a more diffuse plaque conformation and worsening of axonal dystrophy. In this proposal, we aim to explore the possibility that in addition to microglia, the astrocytic reaction to early amyloid aggregates and the coordinated reaction between these two cell types is critical for the overall glial protective function. We will utilize sophisticated super-resolution imaging of mouse and human brain, intravital optical imaging and in vivo single cell manipulations to investigate the cellular and molecular basis of astrocyte and microglia orchestrated interactions and polarization towards amyloid deposits. We will also explore signaling pathways that can be targeted to enhance this neuroprotective glial barrier and reduce AD-associated axonal pathology.


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 = $565,267 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	000	5	12/15/2025	NON-COMPETING CONTINUATION	$565,267
														Subtotal = $565,267

Issue Date FY: 2025 ( Subtotal = $615,514 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	001	4	8/11/2025	NON-COMPETING CONTINUATION	$50,247
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	000	4	11/29/2024	NON-COMPETING CONTINUATION	$565,267
														Subtotal = $615,514

Issue Date FY: 2024 ( Subtotal = $628,075 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	001	3	5/2/2024	NON-COMPETING CONTINUATION	$62,808
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	000	3	11/30/2023	NON-COMPETING CONTINUATION	$565,267
														Subtotal = $628,075

Issue Date FY: 2023 ( Subtotal = $628,075 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	000	2	1/5/2023	NON-COMPETING CONTINUATION	$628,075
														Subtotal = $628,075

Issue Date FY: 2022 ( Subtotal = $628,075 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	000	1	1/12/2022	NEW	$628,075
														Subtotal = $628,075

Grand Total All Awards = $3,065,006

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Mechanisms of axonal protection by astrocytes and microglia inAlzheimer disease

Award Number: R01AG074657

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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