Amelioration of Tau Pathology by Anle138b Rescues Neuronal Function in a Mouse Model of Human Alzheimer's Disease Tau

Ziel/Aim:

Brain clearance of toxic oligomers by small molecules yields a promising therapeutic concept against tau deposition. However, it has not yet been investigated if oligomer modulators have a beneficial effect on metabolic decline of brain function in Alzheimer's disease (AD). Thus, we aimed to investigate the effects of chronic Anle138b treatment on neuronal function in a mouse model containing AD tau by longitudinal measures of ¹⁸F-fluorodeoxyglucose positron-emission-tomography (FDG-PET).

Methodik/Methods:

Eleven hTau mice and ten controls were imaged by FDG-PET at baseline (14.5 months), followed by randomization into treatment and vehicle groups. FDG-PET was repeated after treatment for three months, and brains were analyzed by immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups and the terminal tau load was correlated with FDG-PET findings.

Ergebnisse/Results:

Tau pathology was significantly ameliorated by Anle138b treatment when compared to vehicle (frontal cortex: -53%, p < 0.001; hippocampus: -59%, p < 0.005). FDG-PET revealed a reversal of metabolic decline during treatment, whereas the placebo group showed further deterioration (SUVR: +6 vs. -7%, p = 0.025). Terminal glucose metabolism in hTau mice indicated a strong correlation with the actual tau deposition proven by immunohistochemistry (R = 0.92, p < 0.001).

Schlussfolgerungen/Conclusions:

Oligomer modulation effectively ameliorates tau pathology in hTau mice and has the potential to rescue neuronal brain function. Molecular imaging by PET can serve for monitoring of Anle138b treatment effects.