Metabolic response of microglia to amyloid deposition during Alzheimer's disease progression in a mouse model.

Alzheimer's disease (AD) drives metabolic changes in the central nervous system (CNS). In AD microglia are activated and proliferate in response to amyloid ß 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.

Modulation of Glial Function in Health, Aging, and Neurodegenerative Disease.

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.

Alzheimer's Disease, Sleep Disordered Breathing, and Microglia: Puzzling out a Common Link.

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.

A comparison between chemical and gas hypoxia as models of global ischemia in zebrafish (Danio rerio).

BACKGROUND: Zebrafish models for neurovascular diseases offer new methods for elucidation of molecular pathways to tissue damage. External fertilization and high fecundity provide opportunities for transgenics and other forms of genetic manipulation that are more accessible than offered by mammalian models of disease. Furthermore, behavioral analyses of zebrafish allow for connection of molecular pathways to organismal outputs such as locomotion, learning, and memory. Unfortunately, a zebrafish model of hypoxia-ischemia has been slow to catch on, possibly due to hypoxia exposure protocols that are challenging to reproduce and result in high mortality. METHODS: In this study, we have introduced a predictable and simple method of hypoxia induction, the addition of sodium sulfite to aquarium water. The effects of this treatment on zebrafish locomotion were compared to those of zebrafish exposed to hypoxia induced by nitrogen gas bubbling, a method used in previous reports. RESULTS: We found that hypoxia induced by sodium sulfite significantly impaired locomotion in the hours following treatment, and its effects did not differ from those caused by nitrogen gas hypoxia. CONCLUSION: These results indicate that hypoxia by sodium sulfite represents an effective and easily reproducible method for the study of hypoxia-ischemia in zebrafish.