Chronic GCPII (glutamate‐carboxypeptidase‐II) inhibition reduces pT217Tau levels in the entorhinal and dorsolateral prefrontal cortices of aged macaques

Abstract

IntroductionCurrent approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1‐42 (Aβ1‐42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post‐synaptic, on spines, where they regulate cAMP‐calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally‐occurring tau pathology.MethodsAged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)),Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)),ResultsAged macaques that received 2‐MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2‐MPPA‐ and vehicle‐treated monkeys showed cognitive improvement; 2‐MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2‐MPPA administration, confirmed in dlPFC samples.DiscussionThese data provide proof‐of‐concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism.Highlights Inflammation is a key driver of sporadic Alzheimer's disease. GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium. Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys. GCPII inhibition is a novel strategy to help prevent tau pathology at early stages.

Biomarkers associated with the pathogenesis of Alzheimer’s disease

“…Studies have shown that inflammatory processes in the aging brain lead to phosphorylation of tau proteins in common late-onset AD. “We are able to reduce tau phosphorylation by restoring the regulatory effects that are lost with age and inflammation,” said Arnsten ( Bathla et al, 2023 ). Members of Arnsten’s lab investigated ways to reduce tau phosphorylation early in disease progression, before neurons are damaged.…”

“…Members of Arnsten’s lab investigated ways to reduce tau phosphorylation early in disease progression, before neurons are damaged. Specifically, they focused on the role of GCPll (glutamate carboxypeptidase-II), a brain enzyme involved in inflammation ( Bathla et al, 2023 ). This enzyme weakens the protective effect provided by mGluR3 (metabolized glutamate receptor 3), a receptor on neurons that promotes higher cognitive function.…”

“…This enzyme weakens the protective effect provided by mGluR3 (metabolized glutamate receptor 3), a receptor on neurons that promotes higher cognitive function. In their research, members of Arnsten’s lab investigated ways to reduce tau phosphorylation early in disease progression (before neuronal damage) ( Bathla et al, 2023 ). Specifically, they focused on the role of GCPll (glutamate carboxypeptidase-II), a brain enzyme involved in inflammation.…”

“…Specifically, they focused on the role of GCPll (glutamate carboxypeptidase-II), a brain enzyme involved in inflammation. This enzyme weakens the protective effect provided by mGluR3 (metabolized glutamate receptor 3), a receptor on neurons that promotes higher cognitive function ( Bathla et al, 2023 ).…”

“…In their research, members of Arnsten's lab investigated 10.3389/fncel. 2023.1279046 ways to reduce tau phosphorylation early in disease progression (before neuronal damage) (Bathla et al, 2023). Specifically, they focused on the role of GCPll (glutamate carboxypeptidase-II), a brain enzyme involved in inflammation.…”