Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Impaired activity-dependent protein synthesis in dendrites and pathophysiology in tauopathy

Award Number: R01AG070193
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2027

Group Awards By:

View Award Description

Impaired activity-dependent protein synthesis in dendrites and pathophysiology in tauopathy - PROJECT SUMMARY/ABSTRACT Pathogenic tau in Alzheimer’s disease and related dementias inhibits the plasticity of neuronal connections underlying progressive memory loss. What remains undetermined, however, are the complex and multifactorial molecular events that disrupt synaptic plasticity in neurons with pathogenic tau. This is major gap in our knowledge of the molecular and physiological processes underlying memory loss in Alzheimer’s disease and related dementias. There is a critical need to uncover how plasticity is dysregulated by pathogenic tau to lay the groundwork for new strategies to target plasticity for therapeutic intervention in these diseases. Long-term potentiation (LTP) is a type of plasticity that involves the persistent strengthening of specific connections between neurons in response to increased activity. There is a strong link between memory impairments and obstructed LTP at synapses in transgenic mouse models of Alzheimer’s disease and related dementias, suggesting that the inability of synapses to express LTP is a key factor leading to memory decline. Our preliminary studies suggest that pathogenic tau blocks the activity-dependent de novo protein synthesis in dendrites that is required for LTP expression. Moreover, we found that pathogenic tau downregulates a translation initiation factor that controls activity-dependent mRNA translation during plasticity. The central hypothesis of this proposal is that pathogenic tau blocks the initiation of local protein translation in dendrites and thereby disrupts the dynamics of postsynaptic proteins that establish LTP and the encoding of new memories. To delineate the mechanism by which pathogenic tau inhibits LTP expression, we propose to use both human induced pluripotent stem cell (iPSC)-derived cultured neurons with familial tau mutations, V337M and R406W, that cause dementia and the PS19 tauopathy mouse model. We will establish the effect of pathogenic tau on the active translation of mRNAs into newly synthesized proteins during LTP expression. We will use a combination of methods to monitor the effect of tau on the rate of protein synthesis and on the subset of mRNAs that are actively translated during LTP. We will next determine the impact of pathogenic tau on a critical step in the initiation of protein translation and the extent to which restoring activity-dependent translation initiation can ameliorate LTP and memory impairments in PS19 mice assessed by electrophysiological recordings and behavioral tests of learning and memory. Finally, we will use an unbiased and innovative APEX proteomics approach to establish the impact of pathogenic tau on the dynamic changes in the postsynaptic protein composition during LTP expression that involve both de novo protein synthesis and the reorganization of protein composition to enhance synaptic strength. From these studies, we expect to elucidate the effect of pathogenic tau on dendritic protein synthesis and the regulation of postsynaptic protein dynamics that underlie the complex and multifactorial causes of memory loss in Alzheimer’s disease and related dementias.


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 = $0 )
2026	2025	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	5	6/30/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $771,040 )
2025	2025	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	5	7/28/2025	NON-COMPETING CONTINUATION	$771,040
														Subtotal = $771,040

Issue Date FY: 2024 ( Subtotal = $785,399 )
2024	2024	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	4	7/16/2024	NON-COMPETING CONTINUATION	$785,399
2024	2024	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	001	4	7/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $785,399

Issue Date FY: 2023 ( Subtotal = $784,070 )
2023	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	3	7/25/2023	NON-COMPETING CONTINUATION	$784,070
														Subtotal = $784,070

Issue Date FY: 2022 ( Subtotal = $782,786 )
2022	2022	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	2	7/25/2022	NON-COMPETING CONTINUATION	$782,786
														Subtotal = $782,786

Issue Date FY: 2021 ( Subtotal = $781,545 )
2021	2021	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	1	7/28/2021	NEW	$781,545
														Subtotal = $781,545

Grand Total All Awards = $3,904,840

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Impaired activity-dependent protein synthesis in dendrites and pathophysiology in tauopathy

Award Number: R01AG070193

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer