Aβ oligomers induce pathophysiological mGluR5 signaling in Alzheimer’s disease model mice in a sex-selective manner

Abstract

The prevalence, presentation, and progression of Alzheimer’s disease (AD) differ between men and women, although β-amyloid (Aβ) deposition is a pathological hallmark of AD in both sexes. Aβ-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, we found that mGluR5 exhibits distinct sex-dependent profiles. Specifically, mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aβ oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aβ-mGluR5 interaction did not appear to depend on estrogen, but rather Aβ interaction with cellular prion protein (PrPC), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aβ oligomers, and PrPC was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aβ pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aβ oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. Our findings indicate that mGluR5 does not contribute to Aβ pathology in females, highlighting the complexity of mGluR5 pharmacology and Aβ signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics.

The Density of Group I mGlu5 Receptors Is Reduced along the Neuronal Surface of Hippocampal Cells in a Mouse Model of Alzheimer’s Disease

“…In this study, we detected no significant change in the total protein expression of mGlu 5 , or in its downstream molecules such as G q/11 and PLCβ 1 , in hippocampal plasma membranes of 12-month-old APP/PS1 mice. This is consistent with previous studies using similar methodological approaches and the same AD model, which showed no changes in mGlu 5 expression levels at the same age [ 42 , 43 ]. Similarly, although translation of findings from animals into humans is relatively unsuccessful because animal models do not faithfully reproduce AD pathology, studies of postmortem human brain tissue also showed no changes in the expression level of mGlu 5 , G q/11 and PLCβ 1 in the cerebral cortex in AD, although decreased binding to mGlu receptors and mGlu 1 expression was reported [ 44 ].…”

The pleiotropic roles of autophagy in Alzheimer's disease: From pathophysiology to therapy

“…Interestingly, allosteric inhibition of mGluR5 by CTEP restarted autophagy and rescued Aβ pathology in male APPswe/PS1ΔE9 mice, but not in their female counterparts. This was due to the fact that the aberrant association of mGluR5 with Aβ and PrP C , which leads to the inactivation of the GSK3β–ZBTB16 autophagy pathway, occurs only in the male mouse brain [ 51 ]. In the context of gender-specific pathogenic events, the identification of the oestrogen receptor beta role in promoting autophagy flux by direct interaction with ATG7 might explain why low oestrogen levels during menopause correlate with an acceleration of AD onset [ 52 ].…”

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

“…Remarkably this binding is absent in female (but not male) mice and human tissue. Moreover, mGluR5 inhibition using CTEP does not rescue memory deficits maze in female APPswe/PS1∆E9 mice (Abd-Elrahman et al, 2020a). Generally, the binding of oAβ42 to PRPC is portrayed as the initiating factor in forming the complete oAβ42-PRPC-mGluR5 complex (Brody and Strittmatter, 2018;Nygaard and Strittmatter, 2009;Peters et al, 2015;Smith and Strittmatter, 2017).…”