In the central nervous system (CNS), glial cells, such as microglia and astrocytes, are normally associated with support roles including contributions to energy metabolism, synaptic plasticity, and ion homeostasis. In addition to providing support for neurons, microglia and astrocytes function as the resident immune cells in the brain. The glial function is impacted by multiple aspects including aging and local CNS changes caused by neurodegeneration. During aging, microglia and astrocytes display alterations in their homeostatic functions. For example, aged microglia and astrocytes exhibit impairments in the lysosome and mitochondrial function as well as in their regulation of synaptic plasticity. Recent evidence suggests that glia can also alter the pathology associated with many neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Shifts in the microbiome can impact glial function as well. Disruptions in the microbiome can lead to aberrant microglial and astrocytic reactivity, which can contribute to an exacerbation of disease and neuronal dysfunction. In this review, we will discuss the normal physiological functions of microglia and astrocytes, summarize novel findings highlighting the role of glia in aging and neurodegenerative diseases, and examine the contribution of microglia and astrocytes to disease progression.

Sleep Disordered Breathing (SDB) and Alzheimer’s Disease (AD) are strongly associated clinically, but it is unknown if they are mechanistically associated. Here, we review data covering both the cellular and molecular responses in SDB and AD with an emphasis on the overlapping neuroimmune responses in both diseases. We extensively discuss the use of animal models of both diseases and their relative utilities in modeling human disease. Data presented here from mice exposed to intermittent hypoxia indicate that microglia become more activated following exposure to hypoxia. This also supports the idea that intermittent hypoxia can activate the neuroimmune system in a manner like that seen in AD. Finally, we highlight similarities in the cellular and neuroimmune responses between SDB and AD and propose that these similarities may lead to a pathological synergy between SDB and AD.

Zebrafish models for neurovascular diseases have been developed over the past decade, 1 and several advantages of zebrafish as a laboratory model have been reported. The foremost one is external fertilization that provides up to 200 embryos per instance that are susceptible to genetic manipulation through techniques including Tet-On control systems, morpholino antisense targeting, and CRISPR-Cas9 vector systems. 2-4 Researchers can thus perform high-throughput genetic screens or establish transgenic lines in relatively few generations compared to rodent models. Zebrafish also offer the ability to apply many of the same neurobehavioral assays used in rodents. 5 Assays include measurement of visual discrimination, social behavior, novel object recognition, anxiety, and conditioned place preference. 6-11 Furthermore, the effects of pharmacologic treatments on these behaviors can be

Alzheimer's disease (AD) drives metabolic changes in the central nervous system (CNS). In AD microglia are activated and proliferate in response to amyloid β plaques. To further characterize the metabolic changes in microglia associated with plaque deposition in situ, we examined cortical tissue from 2, 4, and 8-month-old wild type and 5XFAD mice, a mouse model of plaque deposition. 5XFAD mice exhibited progressive microgliosis and plaque deposition as well as changes in microglial morphology and neuronal dystrophy. Multiphoton-based fluorescent lifetime imaging microscopy (FLIM) metabolic measurements showed that older mice had an increased amount of free NAD(P)H, indicative of a shift towards glycolysis. Interestingly in 5XFAD mice, we also found an abundant previously undescribed third fluorescence component that suggests an alternate NAD(P)H binding partner associated with pathology. This work demonstrates that FLIM in combination with other quantitative imaging methods, is a promising label-free tool for understanding the mechanisms of AD pathology.

The in utero environment is well known to influence CNS development and behavioral phenotypes, lasting well into adulthood. However, long‐term neurodevelopmental reprogramming is poorly understood in the context of sleep‐disordered breathing (SDB) during pregnancy despite its increased prevalence in recent years. Neurodegenerative diseases, including Alzheimer’s disease (AD), strongly correlate with the incidence of sleep apnea in humans, a manifestation of SDB. To address this, we utilized a genetic mouse model of Alzheimer’s disease (AD; hemizygous 5xFAD) after in utero exposure to gestational intermittent hypoxia (GIH), a hallmark of SDB during pregnancy. We tested the hypothesis that GIH exposure will exacerbate the neurodegeneration previously described in 5XFAD mice. Pregnant dams received intermittent hypoxia (90s alternating 6.5%/21% O2) or normoxia (90s alternating 21%/21% O2) for 12 hrs/day during their sleep cycle from gestational days 10‐18. At 4, 6, and 8 months of age, offspring were subjected to prefrontal cortex‐ and hippocampal‐dependent behavioral testing to assess disease‐related decline. Preliminary data show GIH‐dependent decline in 5XFAD male offspring and not females. After final behavioral testing, brains were harvested for immunohistochemistry analysis and immunomagnetic microglial isolation. Imaging analysis demonstrated cellular alterations including increased number of microglia and decreased number of astrocytes in 5XFAD females exposed to GIH, which was not seen in males. Studies are underway to analyze microglial immune responses, inflammatory and intercellular communication gene expression by RNA‐sequencing. Together, these data suggest that GIH may exacerbate neurocognitive decline and alter cellular responses to disease that correlates with altered microglial function, in a manner that differs by sex. These observations have implications for people with sleep apnea, particularly during pregnancy and the subsequent brain health of their offspring.

Alzheimer’s disease (AD) is a neurodegenerative disease commonly associated with aging. Along with a decline in cognition and memory, individuals with AD often have respiratory disturbances such as sleep apnea, insufficient ventilation during sleep, and shortness of breath. Mechanisms underlying respiratory dysfunction in AD are unknown but may involve chemosensory deficits since at least one chemosensitive region, the locus coeruleus, undergoes significant neurodegeneration during AD progression in humans. To test the hypothesis that chemoreflexes are impaired in a mouse model of AD, we measured the hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses using whole body plethysmography in 5XFAD mice as amyloid pathology progressed. We evaluated 2 timepoints of amyloid beta (Aß) pathology: early (4 months of age) and late (8 months of age). Compared to WT mice, 8-month-old male and female 5XFAD mice had a significantly reduced capacity to increase ventilation following challenge with 5% inspired CO2 (males: 5XFAD 99 ± 11% vs WT 168 ± 18%; females: 5XFAD 126 ± 12% vs. WT 212 ± 12%) or 5% inspired O2 (males: 5XFAD 141 ± 20% vs. WT 201 ± 20%; females: 5XFAD 75 ± 7.6% vs. WT 134 ± 12%). In addition, both male and female 5XFAD mice experienced significantly more apneic events (~120 apneas per/h) than their WT counterparts (~50 apneas/h) during presumptive sleep. Consistent with impaired ventilation, Aß plaques were abundant in medullary regions of the brainstem where both central chemosensors and rhythm generating neurons reside. Preliminary data suggest that chemoreflex dysfunction may emerge early in disease progression since a trend toward a reduced HCVR (5XFAD 133 ± 23% vs WT 206 ± 39%, combined sexes) was apparent in 4-month-old 5XFAD mice. Surprisingly, and contrary to findings at 8 months, preliminary data in 4-month-old 5XFAD mice indicate that the HVR may be slightly higher indicating that 5XFAD mice may be hypersensitive to hypoxia early in disease progression. Together, these data suggest that responses to ventilatory challenges become significantly disrupted by Aß pathology late in disease progression, deficits which may manifest early in disease and could promote disease progression. Results from our studies will identify the contributions of Aß deposition to respiratory dysfunction in 5XFAD mice, and may have implications for therapeutic interventions in individuals with AD. NIH R01 HL142752, HL142752S1, and T32 AG000213 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.