Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi

Area of Science:

• Neuropathology
• Neurodegenerative Diseases
• Aging Brain Research

Background:

• Intracellular protein aggregates (inclusion bodies) are common in elderly brains.
• TDP-43 and tau protein aggregates often coexist and are linked to cognitive impairment.
• The relationship between inclusion body distribution and diseases like Alzheimer's Disease (AD) remains unclear.

Purpose of the Study:

• To investigate the correlation between inclusion body presence/distribution and underlying diseases, particularly AD.
• To determine if neurofibrillary tangle (NFT) pathology outside the Braak staging system characterizes TDP-43 positive, AD-negative brains (CARTS).
• To examine TDP-43 pathology's association with comorbid AD pathology and argyrophilic grains.

Main Methods:

• Analysis of autopsy brain data from 247 individuals at the University of Kentucky AD Center.
• Focus on brains without frontotemporal lobar degeneration.
• Immunofluorescence experiments on a subsample to assess protein colocalization.

Main Results:

• Hippocampal TDP-43 pathology correlated with advanced AD (Braak NFT stages V/VI).
• Argyrophilic grain pathology was not more frequent in TDP-43 positive cases.
• Brains with CARTS (TDP-43[+]/AD[-]) showed increased NFTs in dentate granule neurons compared to TDP-43[-]/AD[-] cases.
• Approximately 1% of dentate granule neurons were PHF-1 positive in advanced AD and CARTS, while ~25% of TDP-43 positive cells showed colocalized PHF-1.

Conclusions:

• NFTs in hippocampal dentate granule neurons are frequently observed in CARTS.
• These NFTs may serve as a potential biomarker for CARTS in individuals without significant AD pathology.
• TDP-43 pathology might be secondary to or occur concurrently with tauopathy.