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Astrocyte-secreted proteins as modulators of neurodegeneration in Down Syndrome and Alzheimers Disease

Award Number: K99AG081536
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Astrocyte-secreted proteins as modulators of neurodegeneration in Down Syndrome and Alzheimers Disease - Project Summary/Abstract Down Syndrome (DS) is a neurodevelopmental disorder caused by trisomy of chromosome 21, and with age a majority of DS patients develop neuropathological hallmarks associated with Alzheimer’s Disease (AD), including amyloid plaque deposition and astrogliosis, as well as clinical dementia (cooccurrence of DS with AD is DS-AD). Amyloid precursor protein (APP) mutations are linked to AD, and DS patients have triplication of the APP gene, suggesting this as a contributing factor to the overlapping pathology. Research suggests astrocytes are regulators of both DS and AD disease progression. Astrocytes modulate synapses through the release of secreted proteins, and recent work suggests that astrocyte protein secretion is dysregulated in both DS and AD. The Allen lab identified >700 astrocyte-secreted proteins dysregulated in the Ts65Dn mouse model of DS at neonatal timepoints. Of interest, secretion of the pro-growth protein pleiotrophin (Ptn) was >4x down-regulated from Ts65Dn astrocytes, and subsequent investigations of Ptn knockout mice revealed that they phenocopy Ts65Dn mice in many aspects, including decreased dendrite length and spine density. Single nucleus RNA- Sequencing studies show that subsets of “disease-associated” astrocytes in AD down-regulate transcripts encoding for many pro-synaptogenic factors, including Ptn. The main hypotheses of this proposal are that: 1) a network of overlapping astrocyte-secreted proteins is altered in DS-AD and AD, and 2) decreased Ptn secretion from astrocytes contributes to disease progression in DS-AD and AD. This proposal takes an unbiased approach to characterize changes in the astrocyte secretome in DS-AD and AD mouse models, as well as a targeted approach to investigate the potential for Ptn to rescue neuropathological phenotypes. Aim 1/K99 utilizes biotin- mediated proximity labeling (an endoplasmic reticulum localized TurboID virus) to create novel datasets for the in vivo astrocyte-specific secretome in DS-AD and AD mouse models at early, middle and late stages of disease. This aim provides the investigator with extensive training in mass spectrometry technology and quantitative proteomics analysis. Aim 2/R00 employs viral-mediated Ptn overexpression in astrocytes to investigate if Ptn can rescue spine density, astrogliosis and spatial memory impairments in DS-AD and AD mouse models. Additionally, the investigator will utilize the astrocyte-specific secretome datasets from Aim 1 to investigate other protein candidates in their future laboratory. The mentoring team consists of Dr. Nicola Allen, a leader in astrocyte biology; Dr. Alan Saghatelian, who will provide expertise in quantitative proteomics; Dr. Jolene Diedrich, mass spectrometry core director; Dr. Nick Andrews, behavioral core director; and Dr. Douglas Galasko, a neurologist specializing in dementia and Associate Director of the Alzheimer’s Disease Research Center (ADRC) at the University of California San Diego (UCSD). The work will take place at the world class Salk Institute for Biological Studies and establish networking connections at the ADRC and UCSD, providing an essential foundation for Dr. Brandebura’s independent research career focused on astrocyte-secreted proteins in neurodegeneration.


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: 2025 ( Subtotal = $0 )
2025	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	9/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $124,200 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	5/29/2024	NON-COMPETING CONTINUATION	$124,200
														Subtotal = $124,200

Issue Date FY: 2023 ( Subtotal = $124,200 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	5/10/2023	NEW	$124,200
														Subtotal = $124,200

Grand Total All Awards = $248,400

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Astrocyte-secreted proteins as modulators of neurodegeneration in Down Syndrome and Alzheimers Disease

Award Number: K99AG081536

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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