The decline of cognitive function has emerged as one of the greatest health threats of old age. The decline of cognitive function during normal aging is thought to be due to synaptic malfunction rather than loss of synapses or neurons. Although the mechanisms responsible are as yet unknown, the rate of synapse turnover is reduced in the aged brain, suggesting that senescent synapses accumulate with aging contributing to cognitive decline and placing the brain at higher risk for age-associated neurodegenerative diseases such as Alzheimer's disease. In this project, we propose to investigate the cellular and molecular mechanisms that underlie synaptic senescence of normal CNS aging. Specifically, we hypothesize that astrocytes, a major class of central nervous system glia, are critical mediators of synaptic health during aging. Recently, we discovered that astrocytes actively engulf and eliminate synapses in the developing and adult brain. Astrocytes appear to progressively engulf fewer synapses with normal aging. We will specifically investigate the hypothesis that reduced synaptic turnover by astrocytes with aging could lead to exponential accumulation of senescent synapses and cognitive decline and that enhancing this turnover mechanism could prevent or minimize synaptic senescence. First, we will characterize the rate of synapse engulfment by astrocytes in vivo over the lifetime of the brain to confirm that this engulfment rate progressivel declines with normal aging, and also determine whether astrocytes preferentially eliminate different synapse types or synapses in specific neural circuits. Second we will determine the molecular and cellular mechanisms that underlie this decline in engulfment of synapses by astrocytes by genetic profiling and in vitro assays with purified mammalian astrocytes. Finally, we will generate a transgenic mouse that has enhanced astrocyte phagocytosis of synapses to find out whether """"""""speeding up"""""""" astrocyte synapse eating improves cognition during aging. These experiments have the potential to lead to a better understanding of why synaptic senescence occurs in the aging brain, and to lead to new therapies to lessen cognitive decline and vulnerability to Alzheimer's and other neurodegenerative diseases.

Public Health Relevance

One of the greatest health concerns of this century is the prevalence of cognitive decline and dementia. Age-associated changes in cognition are thought to reflect alterations in the stability, strength, and abundance of synaptic connections between neurons, although what drives this process during aging is largely unknown. In this proposal we will investigate how astrocytes, the major class of glia in the brain, mediate synapse elimination with age, which may explain why synapses become senescent with normal aging and are lost during neurodegenerative disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Wise, Bradley C
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Stanford University
Schools of Medicine
United States
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Clarke, Laura E; Liddelow, Shane A; Chakraborty, Chandrani et al. (2018) Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci U S A 115:E1896-E1905
Liddelow, Shane A; Guttenplan, Kevin A; Clarke, Laura E et al. (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481-487
Clarke, Laura E; Barres, Ben A (2013) Glia keep synapse distribution under wraps. Cell 154:267-8
Clarke, Laura E; Barres, Ben A (2013) Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 14:311-21