Targeting astrocytes to prevent motor decline in aging

PROJECT SUMMARY
In the aged brain, reduced brain size and altered synaptic function are observed in conjunction with motor and
cognitive decline. Despite the importance of identifying what underlies these changes with aging, the molecular
drivers of brain aging and synaptic decline are not well characterized. Recently a role for non-neuronal glial cells,
i.e., astrocytes, microglia, and oligodendrocytes, has been proposed in typical aging. Astrocytes are 15% of brain
cells and provide metabolic support for neurons, perform neurotransmitter recycling, and directly modulate
neuronal synapses in the developing and adult brain. Studies show mouse astrocytes undergo regionally-specific
molecular alterations with aging, with unique transcriptional alterations in astrocytes of the cortex, hippocampus,
striatum, hypothalamus, and cerebellum. In particular, astrocytes of the cerebellum show greater transcriptional
dysregulation than those in cortex, including upregulation of immune system genes in the interferon pathway.
Prior work identified loss of cerebellar neurons in aging, raising the question of whether regionally specialized
changes to cerebellar astrocytes that occur with aging contribute to this neuronal decline. To address this
question RNA sequencing of astrocytes from mouse and human, adult and aged, cerebellum was performed,
identifying Stat1 as a candidate transcriptional regulator of the heightened interferon state of cerebellar
astrocytes in the aged brain. Upregulation of Stat1 occurs concomitant with reduced numbers of excitatory
synapses in cerebellum, and mouse behavioral alterations that are linked to cerebellar function. In Aim 1
experiments are performed to ask if Stat1 is responsible for driving the aged astrocyte signature in the cerebellum
by: decreasing expression of Stat1 in astrocytes in aged mice using viral delivery of the RNA degrading enzyme
CasRx to ask if this is sufficient to revert cerebellar astrocyte aging signatures, and rescue synaptic and
behavioral deficits that are present; knocking-out Stat1 from adult astrocytes to ask if this is sufficient to prevent
the induction of aging-related alterations in cerebellar astrocytes; over-expressing Stat1 in cerebellar astrocytes
in juvenile mice to ask if this is sufficient to drive aging-related transcriptional signatures and motor decline. In
Aim 2 experiments address the cues that drive upregulation of Stat1 and the genes it regulates in aged cerebellar
astrocytes, focusing on signaling through the interferon receptor in astrocytes, and asking if the source of
interferon originates within the brain or in the periphery. These experiments will provide mechanistic insight into
the transcriptional regulation of aging-associated astrocyte states and reveal their contribution to synaptic and
behavioral decline in the aging brain.

Grant Number: 1R21AG091117-01
NIH Institute/Center: NIH
Principal Investigator: Nicola Allen