ABSTRACT
Astrocytes control neurotransmission, contribute to the blood-brain-barrier (BBB), and metabolically support
neuronal activity. In Alzheimer’s Disease (AD), astrocytes become reactive near amyloid (A plaques, contribute
to neuroinflammation, and are involved in synaptic and circuit abnormalities. Growing evidence also suggests
astrocyte dysfunction may play a role in early disease progression, but much remains unknown. The relationship
between astrocytes and the BBB is particularly intriguing in AD because vascular dysfunction is a risk factor for
developing AD and reciprocal interactions between astrocytes and the BBB can lead to synergistic dysfunction
in disease progression. In addition, traumatic brain injury, which disrupts astrocyte and BBB function, is a risk
factor for AD and related dementias. Excitatory amino acid transporters (EAATs: GLT-1 and GLAST) and
inwardly rectifying K+ channels, including Kir4.1, give astrocytes two of their fundamental functions, taking up
extracellular glutamate and K+, respectively. Preliminary rodent data in the parent R21 identifies a novel astrocyte
phenotype during normal aging in which progressively more astrocytes lose EAAT and Kir4.1 expression. This
age-related loss is not a gradual, global change but rather occurs on a cell-by-cell basis with individual astrocytes
expressing minimal EAAT and Kir4.1, while neighboring astrocytes remain normal. The appearance of these
“atypical astrocytes” (AtAs) occurs near vasculature and in areas of BBB compromise. In this
supplement request, we propose to extend our studies of AtAs into a mouse model of Alzheimer’s
Disease (AD). AtAs represents a new subtype of astrocytes that could have important implications for brain
function and neurological disease. AtA have been previously reported follow mild traumatic brain injury (mTBI)
and are thought to be associated with injury-related compromise of the BBB. In the parent R21, we reported that
AtAs are also found in the aging brain in specific regions of the cortex and that BBB dysfunction and abnormal
astrocyte glutamate uptake is seen in regions where AtAs are found, showing a functional consequence of AtAs.
In this supplement request, we will utilize the APPNL-G-F mouse model of Alzheimer’s Disease (AD), which
contains 3 human disease-causing mutations in the APP protein. We include preliminary data that AtAs are more
abundant in the hippocampus of APPNL-G-F mice, as compared to WTs. We hypothesize that AtAs are more
common in APPNL-G-F mice due to BBB dysfunction and are associated with the loss of the astrocyte protein
aquaporin-4 (AQP-4). AQP-4 is important in removing A from the brain, so the presence of more AtAs, which
lack AQP-4, could lead to increases in A plaque formation. In addition, we propose to examine the effects of
mTBI in APPNL-G-F mice. Because we suspect that APPNL-G-F mice are prone to BBB dysfunction, we hypothesize
that mTBI will induce increased BBB compromise and lead to more AtAs. If correct, these studies will suggest
AtAs may play a role in the pathology of AD, will link BBB compromise to A plaque formation via AtA, and would
support targeting astrocyte AQP-4 function to reduce AD-related pathology.