# The relationship between sleep apnea and Alzheimer's disease in a unique mouse model: role for microglia

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $381,892

## Abstract

There is a complex, but poorly understood relationship between Alzheimer’s disease (AD) and sleep apnea (SA).
Indeed, about half of individuals with Alzheimer’s disease (AD) also have sleep apnea (SA). Importantly, when
both pathologies are co-morbid, cognitive decline is exacerbated, which takes a severe economic toll and has
significant impact on patient and family quality of life. Indeed, SA is prevalent in almost all neurodegenerative
disorders suggesting that common underlying causal mechanisms are likely involved, given the striking overlap
in patient populations, and the similarities in symptom timing and onset. We propose that the synergy between
AD and SA results from initial over engagement of microglia, CNS resident macrophages that are involved in the
development of both pathologies. In early AD pathology, microglia are recruited to and accumulate around beta
amyloid (Aβ) plaques, initially walling off and protecting the surrounding healthy brain tissue from toxic Aβ
peptides. However, over the course of AD progression, sustained Aβ exposure induces microglial inflammatory
activities, compounding ongoing neuronal damage. Coincidentally, intermittent hypoxia and sleep fragmentation,
both of which are hallmarks of SA, can prime microglial inflammatory and phagocytic activities, also causing
neuroinflammation, microglial activation, and neuronal degeneration. Accordingly, we posit that in the context of
combined SA and AD, the normally protective capacity of microglia to wall the brain off from neurotoxic Aβ, and
phagocytose cell debris, becomes overwhelmed, effectively “exhausting” them metabolically, allowing ongoing
neurodegenerative processes to proceed unchecked. In the parent proposal, we modeled the intermittent
hypoxia aspect of SA in rat dams during gestation (GIH) and found that her adult male offspring spontaneously
developed sleep apnea as adults, which was reflected as an increase in apneas during sleep. Further, microglia
from male GIH offspring had primed inflammatory responses to immune challenges, setting the stage for their
exaggerated immune response with coincident AD pathology. In this supplement, we will test the hypothesis that
adult 5XFAD mice exposed to gestational intermittent hypoxia (GIH) in utero exhibit increased spontaneous
apneas during presumptive sleep, increased microglial exhaustion, and enhanced neurodegeneration with age.
We will evaluate apneas and cognitive dysfunction over time in adult, WT and 5XFAD littermate offspring, as
measures of symptom onset and severity. We will also assess molecular, biochemical and histologic aspects of
microglial function in these offspring. If microglial contributions to these disorders can be understood, they may
represent a novel therapeutic target that can be manipulated to reduce reciprocal, synergistic, disease
interactions between SA and AD. These studies will form the foundation for future R01 studies designed to probe
the mechanistic contributions of exhauste...

## Key facts

- **NIH application ID:** 10288404
- **Project number:** 3R01HL142752-03S1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Tracy L Baker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,892
- **Award type:** 3
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288404

## Citation

> US National Institutes of Health, RePORTER application 10288404, The relationship between sleep apnea and Alzheimer's disease in a unique mouse model: role for microglia (3R01HL142752-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10288404. Licensed CC0.

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