Time-dependent histological characterization of amyloid-β induced cholinergic and glial alterations and their modulation by dehydroepiandrosterone sulfate (DHEAS) - Report - MDSpire
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Time-dependent histological characterization of amyloid-β induced cholinergic and glial alterations and their modulation by dehydroepiandrosterone sulfate (DHEAS)
Temporal Histological Effects of Amyloid-β on Cholinergic and Glial Cells and DHEAS Modulation
Overview
Amyloid-β (Aβ) injection into the nucleus basalis magnocellularis (NBM) induces time-dependent neurotoxic effects on cholinergic neurons and activates microglia and astrocytes. Treatment with dehydroepiandrosterone sulfate (DHEAS) preserves cholinergic fiber density and modulates glial inflammatory responses, suggesting neuroprotective potential.
Background
Alzheimer’s disease (AD) is characterized by amyloid-β accumulation leading to cholinergic neuron degeneration and neuroinflammation. The basal forebrain cholinergic system, particularly the NBM, is vulnerable to Aβ toxicity, which disrupts acetylcholine synthesis and promotes neuronal death. Activated microglia and astrocytes contribute to chronic inflammation in AD, exacerbating neuronal damage. DHEAS, an endogenous steroid, declines with age and AD and may exert neuroprotective and anti-inflammatory effects, making it a candidate for therapeutic intervention.
Data Highlights
Time Post Aβ Injection
Cholinergic Fiber Density
Cholinergic Cell Bodies
Microglia Activation
Astrocyte Reactivity
DHEAS Effects
3 days
Decreased
No significant change
Microglia amoeboid morphology increased
Beginning of astrocyte ramification increase
Preserved fiber density; reduced microglia area and number
12 days
Decreased
No significant change
Elevated microglia activation
Increased astrocyte ramification
Continued modulation of glial response
33 days
Decreased
No significant change
Microglia activation decreased
Astrocyte reactivity normalized
Maintained fiber preservation and reduced microglia
Key Findings
Aβ1–42 injection into the NBM causes time-dependent cholinergic fiber loss without significant loss of cholinergic cell bodies.
Microglial activation occurs early (by day 3) with amoeboid morphology, while astrocyte reactivity increases later (between days 3 and 12).
DHEAS treatment preserves cholinergic fiber density but does not affect cholinergic cell body numbers.
DHEAS reduces microglial activation by decreasing both the area occupied and the number of microglia in a time-dependent manner.
The neuroprotective effects of DHEAS may be mediated through modulation of glial inflammatory responses.
Clinical Implications
These findings suggest that targeting glial activation and preserving cholinergic fibers with agents like DHEAS could be a promising therapeutic strategy in AD. Early intervention to modulate neuroinflammation may mitigate cholinergic dysfunction and slow disease progression. Further studies are needed to clarify DHEAS’s mechanisms and optimize its clinical application.
Conclusion
Aβ induces progressive cholinergic and glial alterations in the NBM, with DHEAS demonstrating potential to preserve cholinergic fibers and attenuate glial activation. This supports further exploration of DHEAS as a neuroprotective agent in AD models.
References
Original Study 2024 -- Temporal Analysis of Histological Changes Induced by Amyloid-β and Regulation by DHEAS
