Cholinotrophic basal forebrain connectome dysfunction in Down syndrome with and without dementia

Area of Science:

• Neuroscience
• Neurodegenerative Diseases
• Genetics

Background:

• Cholinotrophic basal forebrain (CTBF) neurons rely on nerve growth factor (NGF) signaling for survival.
• Down syndrome (DS) involves NGF system dysfunction, but dementia development varies among individuals.
• Understanding NGF pathway differences in demented versus non-demented DS individuals is crucial.

Purpose of the Study:

• To investigate differences in NGF signaling pathways between demented individuals with DS (DSD+) and non-demented individuals with DS (DSD-).
• To compare these pathways to age-matched controls (AMC).

Main Methods:

• Immunohistochemical analysis of p75^NTR and choline acetyltransferase (ChAT) positive neurons in the nucleus basalis of Meynert.
• Quantification of p75^NTR, proNGF, and ChAT protein levels.
• Assessment of tau pathology using AT8 and Thioflavin-S staining.

Main Results:

• DSD+ cases showed significantly reduced p75^NTR positive neurons compared to DSD- and AMC.
• ChAT positive cells were significantly lower in DSD+ than in DSD- and AMC.
• Elevated p75^NTR and proNGF levels, with decreased ChAT levels, were observed in DSD+ compared to AMC.
• Increased AT8 tau and Thioflavin-S positive neurofibrillary tangles were found in DSD+.

Conclusions:

• The p75^NTR/proNGF pathway appears more involved in dementia in individuals with DS.
• Further research is needed to identify factors contributing to cognitive resilience in non-demented individuals with DS (DSD-).