Glial fibrillary acidic protein (GFAP) consistently shows up in proteomic analyses of age-related neurodegenerative processes, particularly now that more research groups are engaged in building early warning biomarker profiles for the later development of Alzheimer's disease. Such studies are usually focused on Alzheimer's disease because that is where most neuroscience funding is directed, but the presence of GFAP as a marker is more generally applicable to the aging of the brain and its supporting cell populations.
Astrocyte cells exhibit increased expression of GFAP when they become reactive, it is a well-known marker of this state. Reactivity occurs in response to damage and altered signaling in the tissue environment characteristic of blood-brain barrier disruption, injury, and neurodegenerative disease. The reactivity of astrocytes is straightforward to describe, in terms of changed expression of markers and changed morphology, but the consequences of reactivity are far from fully mapped at the detail level. Reactivity may overlap with cellular senescence, but not all reactive astrocytes are senescent. The presence of reactive astrocytes is clearly associated with the progression of neurodegenerative conditions, however.
Defining the progression of blood biomarkers of Alzheimer's disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD symptoms in participants in the Baltimore Longitudinal Study of Aging. We show that increased astrocyte reactivity, assessed by elevated glial fibrillary acidic protein (GFAP) levels is an early event in the progression of blood biomarker changes in preclinical AD.
In AD-converters who are initially cognitively unimpaired (N=158, 377 serial plasma samples), higher plasma GFAP levels are observed as early as 10-years prior to the onset of cognitive impairment due to incident AD compared to individuals who remain cognitively unimpaired (N=160, 379 serial plasma samples). Plasma GFAP levels in AD-converters remain elevated 5-years prior to and coincident with the onset of cognitive impairment due to AD. In participants with neuropathologically confirmed AD, plasma GFAP levels are elevated relative to cognitively normal individuals and intermediate in those who remain cognitively unimpaired despite significant AD pathology (asymptomatic AD).
Higher plasma GFAP levels at death are associated with greater severity of both neuritic plaques and neurofibrillary tangles. In the 5XFAD transgenic mouse model of AD, we observed greater GFAP levels in the cortex and hippocampus of transgenic mice relative to wild-type prior to the development of cognitive impairment. Reactive astrocytosis, an established biological response to neuronal injury, may be an early initiator of AD pathogenesis and a promising therapeutic target.
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