Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Amyloid precursor protein (APP) and presenilin 1 (PS1) mutations are linked to Alzheimer's disease pathology.
• Tauopathy is a hallmark of neurodegenerative diseases, often co-occurring with amyloidosis.
• Previous studies showed that over-expressing P301L tau in APP+PS1 mice exacerbates tauopathy.

Purpose of the Study:

• To compare the effects of wild-type (WT) human tau versus aggregation-prone P301L human tau on tauopathy.
• To investigate tau pathology and cognitive function in APP+PS1 mice with mature amyloidosis.
• To determine the in vivo phosphorylation propensity of WT tau versus P301L tau in the context of amyloidosis.

Main Methods:

• APP+PS1 mice were intravenously injected with adeno-associated virus (AAV) vectors expressing either WT or P301L human tau.
• Mice were assessed behaviorally and euthanized at 5 or 9 months post-injection.
• Tau pathology was quantified using ELISA, immunohistochemistry, and human tau mRNA analysis; amyloid pathology was also measured.

Main Results:

• Both WT and P301L tau induced learning and memory deficits in APP+PS1 mice.
• WT tau resulted in less total tau accumulation but a higher proportion of phosphorylated tau (pS396) compared to P301L tau.
• Amyloid pathology levels were not significantly different between groups, suggesting tau phosphorylation is influenced by amyloidosis independently of aggregation propensity.

Conclusions:

• In vivo, WT tau is more susceptible to phosphorylation in the presence of amyloidosis compared to P301L tau.
• Mutant P301L tau may be more prone to aggregation in vitro, but WT tau exhibits increased phosphorylation in vivo.
• Both WT and P301L tau contribute to cognitive impairments in aged mice with established amyloid pathology.