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NIH grant 1R21AG101027-01: The impact of oligodendrocyte APP expression in Alzheimer's disease mouse models
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: ANGELE PARENT. Award: $412500.
Start: 2026-09-05T00:00:00.
Synaptic dysfunction caused by amyloid peptide (Aβ) accumulation contributes to cognitive decline in
Alzheimer's disease (AD). Emerging evidence suggests that neuronal network hyperactivity and asynchrony may
occur very early in the disease process. Network dysfunction has been linked to cognitive impairment and a
defective inhibitory GABAergic system. Supporting this notion, brain seizure activity is frequently observed during
the mild cognitive impairment (MCI) phase in patients with familial AD (FAD)-linked PS1 mutations. Neuronal
hyperactivity also promotes Aβ release. We and others have described aberrant network activity and increased
synaptic transmission in FAD mouse models, which emerge before the onset of overt pathology. We found
exuberant axonal sprouting selectively in the hippocampus of the FAD-linked PS1 mutant knock-in (PS1KI)
mouse model, reminiscent of the aberrant sprouting described in patients with AD. Our results revealed that this
outcome arises from a gain-of-function of amyloid precursor protein (APP)-mediated signaling. APP and the
accumulation of its C-terminal fragments (APP-CTF), through the attenuation of γ-secretase activity associated
with FAD-linked PS1 mutations, promoted neurite outgrowth due to intracellular coupling with adenylate cyclase
and subsequent activation of CREB signaling. Although APP is ubiquitously expressed, transcriptomic analyses
show that APP is most abundant in neurons and oligodendrocytes. Myelinating oligodendrocytes ensheathe
axons to modulate spike timing and circuit activity, which is altered in the early stages of the disease. It is clear
that AD progression toward a more pathological state may involve both neuronal and non-neuronal mechanisms
that have not been fully explored. Accordingly, we hypothesize that the expression of APP and the
accumulation of APP-CTF in oligodendrocytes at a given time during the lifespan may initiate adverse events
at the synapse, compromising brain network activity and contributing to AD pathophysiology. To investigate this
hypothesis, we will examine how the total loss of APP expression, compared to a selective loss of APP in
oligodendrocytes of PS1KI mice: (1) might affect the level of gliosis and changes in synapse formation, and (2)
contribute to the aberration observed in neuronal network activity. We will employ the previously developed APP
knock-out (APPKO), APPfl/fl, and PS1KI mouse lines, and generate an oligodendrocyte-specific APPKO (cKO)
line using the tamoxifen-inducible PLP-CreERT mature oligodendrocyte driver line. To assess the spatiotemporal
outcomes associated with APP expression and APP-CTF accumulation, we will ablate oligodendrocyte APP
expression in young and aging mice. Our goal is to determine whether APP and APP-CTF accumulation in
oligodendrocytes interferes with surrounding cellular components, leading to long-lasting consequences on
synapse function and memory consolidation. This proposal aims to identify new therapeutic targets and broaden
our understanding of the early disease process before Aβ accumulation occurs, with a focus on synaptic
dysfunction, which is the most direct correlate of cognitive decline in AD.document fetched 2026-09-13 02:46