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Investigation of the role of glia cells in Alzheimers pathogenesis in a functional human-based in vitro model

Award Number: R03AG070514
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Investigation of the role of glia cells in Alzheimers pathogenesis in a functional human-based in vitro model - Scientific Abstract / Summary Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder characterized by progressive cognitive decline that leads to age-related dementia. The five approved medications provide only modest symptomatic benefits and provide little effect in halting the disease progression. Improving the mechanistic understanding of disease onset and progression is essential for developing effective AD drugs. Decades of effort have focused on “neuron-centric” mechanisms by targeting amyloid beta (Aβ) and Tau pathologies. Recently neuroinflammation has gained increasing recognition as being an active component in AD etiology. It is becoming crucial to decipher the activation mechanism of astrocytes and microglia, the major players in CNS neuroinflammation, and their interactions with neurons during AD pathology. However, the mechanisms of glial activation and their interplay with neurons is poorly understood, especially in humans, due to the lack of proper models. This study endeavors to develop a human-based functional system that enables the mechanistic study concerning neuron-glia interactions, by taking the advantage of the progress made in induced pluripotent stem cell (iPSC) and Bio-MEMs (microelectromechanical systems) technology. The Specific Aims are: 1) Investigate the functional deficits of cortical neurons derived from AD patients on patterned MEAs, by quantifying the amplitude and maintenance of induced long term potentiation (LTP) and the number of functional synapses, compared to cortical neurons derived from healthy subjects. The longitudinal progression of the phenotype will also be analyzed. Integration of AD-cortical neurons expressing a familial AD gene could uncover the autologous functional phenotype in these neurons. 2) Develop a human-based tri-culture model consisting of human iPSC-derived cortical neurons, astrocytes and microglia, to investigate the neuron- glia interaction in AD. Both the effect of glial cells on the functionality of AD-neurons and the activation status of glia in the tri-culture will be examined. The results will help clarify whether astrocytes and microglia are still protective in the presence of AD-neurons, or becoming toxic at a certain point during the pathological process. The iPSC-sourced feature enables the possibility of patient-specific modeling. The non-invasive MEA system allows chronological monitoring of neural circuit function which is critical to investigate aging-related diseases. Functional readouts, long-term potentiation (LTP) and synapse number have been shown to imitate some clinical cognitive deficits. The model provides an ideal platform for investigating the early pathology and progression of functional impairment of AD-neurons and their interactions with glia. Application of this model could uncover essential mechanisms of glial activation, their interaction with neurons, and reveal potential therapeutic targets for AD. Both the platform and the etiological discoveries could accelerate the development of effective treatments for AD.


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: 2024 ( Subtotal = $0 )
2024	2022	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Aging Research	000	2	5/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $148,185 )
2022	2022	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Aging Research	000	2	2/7/2022	NON-COMPETING CONTINUATION	$133,366
2022	2022	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Aging Research	001	2	4/25/2022	NON-COMPETING CONTINUATION	$14,819
														Subtotal = $148,185

Issue Date FY: 2021 ( Subtotal = $148,185 )
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Aging Research	000	1	1/4/2021	NEW	$148,185
														Subtotal = $148,185

Grand Total All Awards = $296,370

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Investigation of the role of glia cells in Alzheimers pathogenesis in a functional human-based in vitro model

Award Number: R03AG070514

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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