The proposed research will test a novel mechanism for protecting higher cognition and reducing tau
phosphorylation in the aging cortex, based on the unique needs of the newly evolved association cortical
neurons most vulnerable in Alzheimer's Disease (AD). These circuits are powerfully modulated by feedforward,
cAMP-PKA-calcium signaling, which becomes dysregulated with advancing age, leading to: 1) excessive
opening of K+ channels, reducing neuronal firing and impairing cognition, and 2) phosphorylation of tau. Early
stages of tau phosphorylation by PKA can be seen in aged rat association cortex, while more advanced stages
are seen in aged monkey cortex, including fibrillated tau labeled by the AT8 antibody, and accompanying Aß
expression. The proposed research will test a strategy to regulate cAMP-PKA-calcium signaling to reduce AD-
like pathology in the aging cortex by amplifying the brain's natural protective actions at glutamate metabotropic
receptors type 3 (mGluR3). mGluR3 have neuroprotective actions on astrocytes, and additional, regulatory
actions on neurons. New data have revealed post-synaptic mGluR3 in prefrontal association cortex (PFC) that
regulate cAMP-PKA-calcium signaling. The proposed research will enhance stimulation of mGluR3 by its
endogenous ligand, NAAG (N-acetylaspartyl-glutamic acid), via inhibition of the enzyme that destroys NAAG,
GCPII (glutamate carboxypeptidase II). GCPII inhibitors are under development for treating inflammatory
disorders, with excellent tolerability and minimal side effects in phase I human testing. We will observe whether
mGluR3 are positioned to regulate cAMP-PKA phosphorylation of tau in the primate entorhinal cortex (ERC)
and PFC circuits most vulnerable in AD, and whether GCPII inhibition can restore neuronal firing, improve
cognitive function, inhibit phosphorylation of tau, and reduce neuroinflammation in aged rats and monkeys.
This work will confirm and extend the efficacy of two structurally distinct GCPII inhibitors, 2-MPPA and 2-
PMPA, under development by the Johns Hopkins Drug Discovery group. Aim 1 will use dual immunoelectron
microscopy to confirm that mGluR3 are correctly positioned to regulate cAMP-PKA phosphorylation of tau
(pS214Tau) and AT8-labeled tau in aging ERC and PFC glutamatergic synapses. Aim 2 will test whether
acute administration of 2-MPPA or 2-PMPA enhances memory-related PFC neuronal firing in aging monkeys
by regulating cAMP-PKA opening of K+ channels, and whether systemic administration can improve cognition
in aged rats and monkeys with minimal side effects. Aim 3 will test whether chronic treatment with an optimal
dose of 2-MPPA produces sustained improvement in working memory, and reduces tau phosphorylation and
neuroinflammation in aged rat and monkey association cortex. We will have the rare opportunity to see if
chronic 2-MPPA treatment in aged monkeys reduces both fibrillated AT8-labeled tau, and Aß expression.
Preliminary data indicate that these agents produce very robust improvements in cognition with no evidence of
side effects, encouraging a therapeutic strategy with feasible translational application.