Abstract
Microglia and astrocytes play important roles in mediating the immune processes and nutritional support in the central nervous system (CNS). Neuroinflammation has been indicated in the progression of neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD). Chronic neuroinflammation with sustained activation of microglia and astrocytes may affect white matter tracts and disrupt communication between neurons. Recent studies indicate astrogliosis may inhibit remyelination in demyelinating disorders such as multiple sclerosis. In this study, we investigated the relationship between neuroinflammation and myelin status in postmortem human brain tissue (n = 15 including 6 AD, 5 PD, and 4 age-matched, neurologically normal controls (NC)). We conducted systematic and quantitative immunohistochemistry for glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), amyloid beta, and highly phosphorylated tau (tauopathy). White matter intactness was evaluated by myelin and axon staining in adjacent brain tissue sections. Eight of 15 cases (4 AD, 3 PD, and 1 NC) showed increased immunoreactivity for microglia and astrocytes in the white matter that connects striatum and cortex. Quantitative analysis of these 8 cases showed a significant negative correlation between GFAP (but not Iba-1) and myelin (but not axon) staining in white matter (r2 = 0.78, p < 0.005). Tau, but not amyloid beta plaques, is significantly higher in AD vs. PD and NC. Tau burden increases with age in AD cases. These observations indicate that astrocytosis in white matter is associated with loss of myelin in AD, PD, and normal aging and that tau is a potent biomarker for AD.
Highlights
White matter disease is a common pathology involved in the dementia of Alzheimer’s disease [1, 2], multiple sclerosis [3], and cerebrovascular disease [4]
We examined 15 autopsied human brains that included 5 cases of Parkinson disease (PD), 6 cases of Alzheimer disease (AD), and 4 cases of age-matched cognitively normal controls (NC) using immunohistochemistry (IHC) staining for glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1), Aβ and phosphorylated tau, and α-SMA, as well as myelin and axon staining
We found that cases with high GFAP expression (4 Alzheimer’s disease (AD), 3 Parkinson’s disease (PD), and 1 NC) in superficial white matter have a significantly negative correlation with myelin loss, whereas cases with low GFAP expression (2AD, 2 PD, and 3 NC) do not present negative correlation
Summary
White matter disease is a common pathology involved in the dementia of Alzheimer’s disease [1, 2], multiple sclerosis [3], and cerebrovascular disease [4]. We examined 15 autopsied human brains that included 5 cases of Parkinson disease (PD), 6 cases of Alzheimer disease (AD), and 4 cases of age-matched cognitively normal controls (NC) using immunohistochemistry (IHC) staining for GFAP and Iba, Aβ and phosphorylated tau, and α-SMA, as well as myelin and axon staining. Ese data suggest that chronic inflammation-induced astrocytosis in superficial white matter might be associated with myelin impairment and disease progression in these patients. It suggests that tau is a more potent biomarker than Aβ for aging-associated dementia in AD
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