Investigating the Potential Neuroprotective Effects of ACMSD Across Sex in P301S Mice

The kynurenine pathway (KP) is a biosynthetic pathway for the catabolism of tryptophan, the amino acid precursor to serotonin. The KP has been linked to neuroinflammation, as inflammatory agents upregulate an early enzyme in the pathway (Davis & Liu, 2015; Wang et al., 2009). In addition, the metabolite quinolinic acid (QA) has been found to induce tau phosphorylation and excess glutamate release, inducing further neuroinflammation (Guillemin, 2012; Rahman et al., 2009). However, in the presence of 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD), the KP shifts away from QA production towards that of picolinic acid (PA), a metabolite with antimicrobial and antiviral properties. Our lab has previously shown that overexpressing ACMSD via adeno-associated virus (AAV) delivery in the alpha-synuclein (α -syn) model of Parkinson's disease (PD) animal model exhibits neuroprotective effects by preventing the loss of dopaminergic neurons in the substantia nigra and limiting motor impairments caused by nigrostriatal denervation. Based on these findings, we predicted that ACMSD would provide neuroprotective effects in the P301S tauopathy model of neurodegenerative disease, a mouse model of frontotemporal dementia (FTD). Specifically, we hypothesized that ACMSD would ameliorate behavioral deficits, including those related to cognitive and emotional processing. We also predicted that ACMSD overexpression would prevent histological indices of pathology, including the expression of hyperphosphorylated tau, gliosis, and neurodegeneration. As previous findings in the literature have denoted sex differences in pathological outcomes of the P301S mouse model (Sun et al., 2020) with males showing more pronounced behavioral deficits and increased hyperphosphorylated tau than females, we hypothesized that ACMSD would show a higher degree of neuroprotection in male P301S mice. P301S and litter/age-matched wild-type controls underwent stereotaxic surgery at two months of age prior to pathological onset to deliver either an AAV-dHS-ACMSD or AAV-dHS-GFP (control) to the dorsal hippocampus. Prior to euthanasia, the mice underwent the Barnes maze test to assess cognitive function focusing on learning and memory recall. Analysis of this assay revealed that male P301S mice treated with ACMSD displayed a trend toward shorter latency in locating the escape hatch during the Barnes Maze test than untreated males, albeit not significant, suggesting a potential enhancement in spatial learning. At eight and a half months, the mice were killed, and their brains harvested. The tissue underwent immunohistochemistry staining for a marker of hyperphosphorylated tau (AT8), markers of gliosis (Iba1 and GFAP), and the pan-neuronal marker (HuC/D) to quantify pathological indices. Preliminary histological analyses show decreased immunoreactivity of AT8 in the hippocampus of P301S mice injected with ACMSD, compared to those injected with GFP control, indicating potential neuroprotective effects by limiting the amount of hyperphosphorylated tau.