Basic Science and Pathogenesis

We have previously reported that APP+PS1 mice can enhance tauopathy when injected with a virus over-expressing P301L tau. Here we compare the extent of tauopathy produced by the aggregation prone human P301L tau with wild type tau in the presence of mature amyloidosis.

Ten-month-old transgenic mice over-expressing mutant amyloid precursor protein and presenilin 1 (APP+PS1) were injected intravenously with AAV.Cap-B10 over-expressing either wild-type (AAV-WT) or P301L (AAV-P301L) 4R2N human tau. Half of the mice were behaviorally assessed four months post-injection and euthanized five months post-injection. The remaining mice were euthanized nine months post-injection. Pathology was assessed by ELISA and immunohistochemistry.

By ELISA, measures of soluble total tau showed reduced levels in mice injected with AAV-WT compared with AAV-P301L at both five- and nine-month survival times. However, in both cohorts, there was significantly more soluble pS396 tau in AAV-WT mice relative to AAV-P301L, while soluble pS199 tau was significantly increased in AAV-WT mice in only the younger cohort. Measures of insoluble total tau were reduced in AAV-WT compared to AAV-P301L mice, yet insoluble phospho-tau levels were similar in both cohorts. Similarly, histological measures of total tau (HT7) show reduced levels in mice injected with AAV-WT relative to AAV-P301L in both the cortex and hippocampus. However, we observed increased area staining of AT8-positive phospho-tau in mice injected with AAV-WT compared with AAV-P301L. In agreement with our protein measures, we observed significantly less human tau mRNA in mice injected with AAV-WT compared to AAV-P301L. ELISA measures of amyloid pathology were not significantly different between groups. Both AAV-WT and AAV-P301L mice displayed similar learning impairments compared to nontransgenic mice.

Over-expression of both wild-type and P301L tau induced learning and memory deficits in middle-aged APP+PS1 mice with mature amyloid pathology. While we observed less total tau in mice injected with AAV-WT than AAV-P301L, a greater fraction of the total available pool of tau was phosphorylated in mice over-expressing wild-type tau. These data suggest that although mutant P301L tau may be more prone to aggregation in vitro, WT-tau is more prone to phosphorylation in vivo in the presence of amyloidosis.