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Dissecting amyloid β- and tau-mediated dopamine neuron deficits in Alzheimer's disease

Award Number: F32AG097386
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/04/2027
PERIOD OF PERFORMANCE END DATE: 03/03/2028

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Dissecting amyloid β- and tau-mediated dopamine neuron deficits in Alzheimer's disease - PROJECT SUMMARY Alzheimer’s disease (AD) is a complex progressive disease that currently has no early markers for diagnosis and intervention. Classically, AD has been associated with memory impairment due to hippocampal degeneration. However, patients early in disease can experience psychiatric symptoms like anxiety and depression. One brain area that may be responsible for the psychiatric symptoms is the ventral tegmental area (VTA). The VTA contains dopamine releasing neurons that fire action potentials automatically in a slow rhythm but also fire in bursts during behavior events, synchronizing dopamine release with behavior. Recent work from our lab and others shows that AD mouse models with Aβ and tau pathology develop deficits in VTA dopamine neurons including irregular faster firing, synaptic connectivity, and dopamine release. While it is clear Aβ and/or tau plays a role, how dopaminergic neurons progress in pathology and how dopamine release is affected during behavior remains unknown. I have begun investigating separate AD models with either Aβ (APPNL-G-F) or tau (DATCre:AAV-hTau) pathology. In the Aβ model of AD, I found that VTA dopamine neurons exhibit decreased inhibitory connectivity. However, it remains unknown how and when the decrease in inhibitory connectivity forms. In contrast, VTA dopamine neurons in the tau model of AD show faster, more irregular autonomous firing. In addition, the VTA neurons in the tau model appear to be unable to sustain burst firing. These findings suggest that tau pathology may contribute to both decreased reward learning ability and anxiety in models of AD. Based on my preliminary data from these two models, I hypothesize that Aβ is responsible for GABAergic synapse loss from the RMTg, while tau alters dopamine neuron firing leading to decreased phasic release in VTA projection areas. To answer this hypothesis, I plan to 1) Identify the GABAergic inputs reduced by Aβ in the APPNL-G-F model, and 2) Quantify decreased dopamine release in target areas and monitor hTau pathology development. I will determine if the Aβ synaptic decrease is pre- or post-synaptic; identify whether known inhibitory projections to the VTA are lost; and if the synaptic decrease is present through animal development or if synapses decrease in number when mice are “adults”. I will also see if anxiety changes when the synaptic decrease is observed. I will determine the effects of tau pathology on dopamine release in target areas first by virally expressing a dopamine sensor (GRAB_rDA) in VTA projection areas prominent in AD pathology (hippocampus and nucleus accumbens, NAc). I will selectively stimulate VTA dopamine neurons with channelrhodopsin in these projection areas and visualize dopamine release. Next, I will trace and count dopamine neuron axons projecting to the hippocampus. Finally, I will monitor the development of tau pathology from 1 to 8 weeks. Key training in neurodegeneration and 2-photon microscopy are crucial for my progression to independence and are necessary for this project to uncover roles of Aβ and tau in dopamine neuron excitability, highlighting circuits for early intervention.


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 = $65,271 )
2026	2026	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	9/4/2026	NEW	$65,271
														Subtotal = $65,271

Grand Total All Awards = $65,271

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Dissecting amyloid β- and tau-mediated dopamine neuron deficits in Alzheimer's disease

Award Number: F32AG097386

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/04/2027

PERIOD OF PERFORMANCE END DATE: 03/03/2028

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