Time-dependent histological characterization of amyloid-β induced cholinergic and glial alterations and their modulation by dehydroepiandrosterone sulfate (DHEAS)

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Abstract
Introduction: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by predominant - but not exclusive - pathological accumulation of amyloid-β (Aβ) in the brain. This process affects not only neurons (particularly cholinergic) but also glial cells, contributing to progressive neuronal loss and neuroinflammation. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are endogenous steroids that are hypothesized to exert neuroprotective and anti-inflammatory effects. This study aims to histologically characterize the in vivo temporal progression of Aβ-induced alterations in cholinergic neurons and glial morphology. Our secondary aim was to evaluate whether DHEAS protects cholinergic integrity and, if so, whether this effect is mediated through glial activation. Methods: Aβ 1–42 was injected into the cholinergic nucleus basalis magnocellularis (NBM) region of C57BL6/J male mice and one hour later 10 mg/kg DHEAS or vehicle (0.9% saline) was applied intraperitoneally. After 3, 12 or 33 days, the mice were transcardially perfused and immunohistochemical staining was used to investigate cholinergic cell (ChAT) and fiber (AChE) loss, as well as microglia (IBA1) and astrocyte (GFAP) morphology. Results: Our findings confirmed that Aβ peptide exerted neurotoxic effects on the cholinergic system and triggered time-dependent activation in both glia cell types. Microglial cells initiated their response by day 3, adopting an amoeboid morphology, whereas delayed astrocytic reactivity was observed between days 3 and 12, demonstrated by increased ramification. DHEAS treatment preserved cholinergic fiber density, without effecting the number of cell bodies and modulated the inflammatory responses of glia cells, by decreasing the area occupied and number of microglia in a time dependent manner. Discussion: Aβ toxicity exerts time-dependent effects on both cholinergic neurons and glia cells, while DHEAS shows therapeutic promise, though its efficacy and exact mechanism require further investigation.

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