Dystrophic neurites in TgCRND8 and Tg2576 mice mimic human pathological brain aging

Area of Science:

• Neuroscience
• Pathology
• Genetics

Background:

• Beta-amyloid (A beta) plaques are key features in Alzheimer's disease (AD) pathology.
• Dystrophic neurites surrounding A beta plaques are a common observation in AD brains.
• Understanding the precise nature of neuritic pathology in AD models is crucial for therapeutic development.

Purpose of the Study:

• To compare the morphology and neurochemistry of A beta plaque-associated dystrophic neurites in TgCRND8 and Tg2576 mouse models with human AD and aged cases.
• To evaluate the utility of these mouse models for studying early brain changes in AD.

Main Methods:

• Immunohistochemical analysis of brain tissue from TgCRND8 and Tg2576 mice, pathologically aged human cases, and human AD cases.
• Labeling for alpha-internexin, neurofilament triplet, and hyperphosphorylated tau to identify dystrophic neurites.
• Quantification of A beta plaque-associated axonal and dendritic pathology in transgenic mice.

Main Results:

• TgCRND8 and Tg2576 mice exhibited ring- and bulb-like dystrophic neurites labeled with alpha-internexin and neurofilament triplet, similar to aged human cases but distinct from AD cases.
• AD cases showed abundant hyperphosphorylated tau-labeled dystrophic neurites, which were absent in the transgenic mice and aged cases.
• A beta plaques in TgCRND8 mice were highly axonopathic, with associated displacement or clipping of dendritic segments in both mouse models.

Conclusions:

• The neuronal pathology in TgCRND8 and Tg2576 mice closely resembles early, age-related changes associated with A beta plaques, rather than the advanced pathology seen in human AD.
• These transgenic mouse models provide a valuable platform for investigating the early axonal and dendritic pathologies in AD.
• The findings support the use of these models for developing and testing therapeutic strategies targeting the initial stages of AD-related neurodegeneration.