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Septhohippocamal connectome dysfunction in Down syndrome associated with Alzheimer’s disease pathophysiology

Award Number: R01AG077103
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Septhohippocamal connectome dysfunction in Down syndrome associated with Alzheimer’s disease pathophysiology - ABSTRACT Down syndrome (DS) is caused by triplication of human chromosome 21 and results in physical and cognitive developmental delay and disability. Individuals with DS transition to Alzheimer’s disease (AD) in early midlife and develop premature dementia along with histopathological hallmarks of AD including amyloid-beta and tau pathology, synaptic deficits, and neurodegeneration. This sequence of pathological hits preferentially impacts vulnerable neural networks such as the septohippocampal and basocortical circuits which support attention, memory, and executive function. While DS and AD phenotypes overlap in many respects, the extent of shared cellular pathophysiological mechanisms remains poorly understood. The knowledge gap is a potentially missed opportunity to arrest the onset of AD dementia in DS. We propose to identify molecular, cellular, and physiological substrates underlying vulnerability of the septohippocampal and basocortical connectomes in trisomic (Ts65Dn) mice, which faithfully reproduce circuits with memory and executive function deficits in human DS and AD. In parallel, we will study human induced neurons (HiN) derived directly from DS, AD, and control fibroblasts to reveal functional consequences of transcript-level alterations in human neurons. Our cell and animal model findings will be validated in postmortem human brain. Specifically, we propose to identify molecular and cellular substrates underlying calcium signaling and mitochondrial network dynamics within the septohippocampal and basocortical connectomes in young {~4 months of age (MO), middle age (~12 MO) and older (~18 MO)} Ts65Dn mice relative to normal disomic (2N) littermates and in HiN from DS, AD, and age- matched controls. We will evaluate physiological and synaptic signaling properties of septohippocampal and basocortical neurons in acute mouse brain slices and HiN. We will compare expression profiles from these models to neurons obtained postmortem from individuals with DS, AD, and controls. In Aim 1 we will test the hypothesis gene expression pathways regulating calcium handling, oxidative phosphorylation, and synaptic signaling within basal forebrain cholinergic neurons (BFCNs) precede defects in hippocampal and frontal cortical pyramidal neurons in trisomic mice. In Aim 2 we will test the hypothesis differential gene expression pathways in DS manifest as progressive defects in synaptic and calcium signaling, mitochondrial dysfunction, and protein mishandling in DS cell and animal models. In Aim 3 we will test the hypothesis dysregulated genes and pathways in trisomic mice are significantly altered within HiN and analogous postmortem neuronal populations in individuals with DS and AD. This multidisciplinary approach combining single population RNA- sequencing with electrophysiological interrogation enables a determination of the pathobiology underlying BFCN, CA1, and cortical neuron vulnerability in vivo in Ts65Dn and 2N littermates compared to HiN and postmortem human DS neurons with co-occurring AD pathology. We posit these previously unavailable findings will generate new therapeutic strategy approaches for DS and 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: 2026 ( Subtotal = $805,422 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	2	2/5/2026	EXTENSION WITH OR WITHOUT FUNDS	$724,879
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	001	2	3/16/2026	EXTENSION WITH OR WITHOUT FUNDS	$80,543
														Subtotal = $805,422

Grand Total All Awards = $805,422

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Septhohippocamal connectome dysfunction in Down syndrome associated with Alzheimer’s disease pathophysiology

Award Number: R01AG077103

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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