Here is the reformatted version of the article, styled for clarity and readability.
Two Studies Target Alzheimer’s Cellular Mechanisms: Astrocytes and Microglia in Focus
Two independent studies published in November 2025 shed new light on Alzheimer's disease by examining separate cellular mechanisms in mouse models. One focuses on enhancing the cleanup function of astrocytes, while the other identifies microglia as the primary driver of sleep loss.
Study 1: Boosting Astrocytic Sox9 Enhances Amyloid Clearance
Source: Baylor College of Medicine | Nature Neuroscience (November 21, 2025)
The Core Discovery
Increasing the expression of the protein Sox9 in astrocytes significantly enhanced the cells' ability to remove amyloid plaques and maintain cognitive function in Alzheimer's mouse models.
How It Works
- Researchers manipulated Sox9 expression in mice that already exhibited cognitive impairment and amyloid plaques.
- Increasing Sox9 led to greater astrocyte structural complexity and increased ingestion of plaques via the MEGF10 receptor, reducing amyloid buildup.
- Decreasing Sox9 resulted in faster plaque accumulation and simpler astrocyte structure.
"Increasing Sox9 expression triggers astrocytes to ingest more amyloid plaques."
— Dr. Benjamin Deneen, corresponding author
Cognitive Outcomes
Mice with higher Sox9 levels performed significantly better on memory and recognition tests over a six-month period.
Why This Matters
The study was conducted after plaques had already formed, making it more clinically relevant to Alzheimer's patients. Dr. Dong-Joo Choi, first author (now at UTHealth Houston), noted that this approach focuses on enhancing the brain's natural cleanup function rather than solely targeting plaque formation.
Background on Astrocytes
Astrocytes are star-shaped glial cells that support neuronal function, communication, and memory storage. Their function alters with aging. Sox9 is a transcription factor that regulates multiple genes in aging astrocytes, making it a potential therapeutic target.
Funding & Publication
The research was supported by the NIH, the David and Eula Wintermann Foundation, and the Eunice Kennedy Shriver National Institute of Child Health & Human Development.
DOI: 10.1038/s41593-025-02115-w
Study 2: Depleting Microglia Restores Sleep in Alzheimer’s Models
Source: University of Kentucky | Alzheimer's & Dementia
The Core Discovery
Brain immune cells called microglia were identified as a primary driver of sleep loss in Alzheimer's mouse models. Temporarily removing them restored over two hours of sleep per day.
How It Works
- The team used the drug Pexidartinib (PLX3397) to temporarily remove 87% of microglia in mice with amyloid pathology.
- Sleep restoration occurred without a reduction in amyloid plaque levels.
- The research suggests that sleep disruption plateaus early in the disease; deficits observed at six months did not worsen by 18 months, despite a doubling of plaque burden.
"This study identifies EEG signatures that may distinguish Alzheimer's-related sleep changes from normal aging."
Sleep Stage Specificity
Alzheimer's pathology was found to selectively impair NREM (restorative) sleep, while normal aging was associated with reductions in REM sleep. This distinction suggests a potential biomarker for the disease.
Methods Used
- EEG/EMG headmounts tracked sleep stages (NREM, REM, wake).
- Light-sheet microscopy created 3D maps of plaques and microglia.
- A mathematical algorithm (FOOF) separated periodic from aperiodic brain activity.
Future Implications
Future work aims to calm microglia using existing drugs like Metformin or Stiripentol rather than eliminating them. The findings also suggest portable EEG could serve as a non-invasive biomarker for early Alzheimer's screening.
Attribution
- Lead author: Nicholas J. Constantino, PhD (recent University of Kentucky graduate).
- Senior author: Shannon L. Macauley, PhD, associate professor of physiology, UK College of Medicine.