mGluR5 regulates ZBTB16 pathway of autophagy in Alzhimer's disease in a sex-specific manner

Alzheimer's disease (AD) is characterized by neurotoxicity mediated by the accumulation of beta amyloid (Aβ) oligomers, causing neuronal loss and progressive cognitive decline. We have previously showed that genetic deletion or chronic pharmacological inhibition of mGluR5 by the negative allosteric modulator CTEP, rescued cognitive function and reduced Aβ aggregation in male APPswe/PS1ΔE9 (APPswe) mouse model of AD 1,2. We have recently reported that the novel ZBTB16‐medaited mechanism of autophagy downstream of mGluR5 plays a key role in Huntington's disease (HD) pathology in zQ715 mice 3. In a follow‐up study, we showed that the favorable outcomes of mGluR5 silencing either genetically and pharmacologically in male APPswe were associated with a reduction in ZBTB16 similar to zQ175 mice 4. Here, we show that, unlike male mice, chronic (12 week) treatment with CTEP of female APPswe mice does not improve cognitive function or AD pathology. CTEP treatment did not mitigate memory deficits detected in female APPswe mice during novel object recognition and Morris water maze tasks. We then tested brain samples from male and female APPswe mice following 12‐week treatment with either vehicle or CTEP (2mg/kg) for changes in the autophagic clearance of Aβ oligomers via ZBTB16 pathway. When quantified using ELISA, both male and female APPswe mice exhibited higher level of Aβ oligomers at 6 months of age compared to control. To our surprise, CTEP significantly reduced Aβ burden in male mice yet, it exacerbated Aβ oligomers accumulation in female APPswe mice. mGluR5 blockade in male APPswe mice caused a GSK3β‐dependent degradation of ZBTB16 and stabilization of the autophagy adaptor ATG14. This was paralleled by a reduction in the autophagy marker p62. Interestingly, we did not detect any change in GSK3β phosphorylation, ZBTB16, ATG14 or p62 levels in female APPswe mice following CTEP treatment compared to control. It is worth noting that female APPswe brain also exhibited lower expression of mGluR5 compared to age‐matched APPswe male mice. This study supports the inhibitory role of mGluR5 on autophagy via GSK3β/ZBTB16 pathway that result in impaired clearance of Aβ burden in male APPswe only. We also provide evidence, and for the first time, that some aspects of mGluR5 signaling are not conserved between males and females and there are sex‐specific differences that must be considered when embracing mGluR5 as a potential drug target for neurodegenerative disease. Support or Funding Information Alberta Innovates Health Solutions and Canadian Institutes for Health Research This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .