Chronic glial activation causes cholinergic cell loss in the basal forebrain during pathological aging

Abstract

AbstractBackgroundNeuroinflammation, described by chronic glial reactivation lead to gradual neurodegeneration during pathological aging, contributing to disorders like Alzheimer’s disease (AD). Cholinergic cell loss in the basal forebrain (BF) including the medial septum (MS) is associated with AD; however the underlying mechanism is still unknown. Hence, this study investigated the effects of aging and chronic neuroinflammation on the MS cholinergic cell numbers and morphology.MethodAged, 12 and 24 months WT and GFAP‐IL6 mice (presenting IL‐6 overexpression under the GFAP promoter, resulting in chronic glial activation) were used. Immunohistochemistry combined with unbiased stereology and 3D morphology analysis were used to estimate the number and morphology of Iba1+ microglia and ChAT+ cholinergic cells in the MS. Transcriptomic analysis of the MS was performed using qPCR.ResultStereological estimation of MS microglia number displayed a significant 25% increase in GFAP‐IL6 mice compared to control WT (12M). A significant 30% increase was obtained for GFAP‐IL6 (24M) mice compared to control (24M). Furthermore, a significant 23% increase in microglia was described for GFAP‐IL6 (24M) compared to the GFAP‐IL6 (12M) mice. A significant 28% and 38% decrease in microglial 3D surface area, and volume respectively were observed between WT and GFAP‐IL (12M) mice, as well as 26% and 34% decrease respectively between WT (12M) and (24M), resembling reactive microglial morphology. Meanwhile, cholinergic cell number displayed a significant 31% decrease in GFAP‐IL6 (12M) mice compared to WT (12M). While a significant 30% decrease was displayed in GFAP‐IL6 (24M) mice compared to WT (24M) mice. There was a tendency for the cholinergic cell number to decrease with ageing among control and GFAP‐IL6 cohorts. Cholinergic cell morphology displayed significant 58% and 67% reduction in the 3D dendritic field surface area, and volume respectively between WT (12M) and GFAP‐IL (12M) mice, as well as 41% and 46% decrease respectively between WT (12M) and (24M), displaying patterns like neuronal degeneration.ConclusionThese findings demonstrate a significant impact of both aging and chronic glial activation alone on cholinergic cell number and morphology in the MS, resembling the cholinergic cell loss in AD, which can exacerbate throughout ageing leading to neurodegenerative impairments.