Tau accumulation remains one of the closest correlates of neuronal loss in Alzheimer's disease. In addition, tau associates with several other neurodegenerative diseases, collectively known as tauopathies, in which clinical phenotypes manifest as cognitive impairment, behavioral disturbances, and motor impairment. Polyamines act as bivalent regulators of cellular function and are involved in numerous biological processes. The regulation of the polyamines system can become dysfunctional during disease states. Arginase 1 (Arg1) and nitric oxide synthases compete forl-arginine to produce either polyamines or nitric oxide, respectively. Herein, we show that overexpression of Arg1 using adeno-associated virus (AAV) in the CNS of rTg4510 tau transgenic mice significantly reduced phospho-tau species and tangle pathology. Sustained Arg1 overexpression decreased several kinases capable of phosphorylating tau, decreased inflammation, and modulated changes in the mammalian target of rapamycin and related proteins, suggesting activation of autophagy. Arg1 overexpression also mitigated hippocampal atrophy in tau transgenic mice. Conversely, conditional deletion of Arg1 in myeloid cells resulted in increased tau accumulation relative to Arg1-sufficient mice after transduction with a recombinant AAV–tau construct. These data suggest that Arg1 and the polyamine pathway may offer novel therapeutic targets for tauopathies.

In Parkinson's disease, α-synuclein is known to activate microglia and this activation has been proposed as one of the mechanisms of neurodegeneration. There are several signals produced by neurons that have an anti-inflammatory action on microglia, including CX3CL1 (fractalkine). We have shown that a soluble form of CX3CL1 is required to reduce neuron loss in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and that fractalkine agonism can reduce neuron loss in a 6-hydroxydopamine lesion model. Here, we show that fractalkine can reduce α-synuclein-mediated neurodegeneration in rats. Rats that received fractalkine showed abrogated loss of tyrosine hydroxylase and Neu-N staining. This was replicated in animals where we expressed fractalkine from astrocytes with the glial fibrillary acid protein (GFAP) promoter. Interestingly, we did not observe a reduction in MHCII expression suggesting that soluble fractalkine is likely altering the microglial state to a more neuroprotective one rather than reducing antigen presentation.

Alzheimer's disease is characterized by amyloid plaques, neurofibrillary tangles, glial activation, and neurodegeneration. In mouse models, inflammatory activation of microglia accelerates tau pathology. The chemokine fractalkine serves as an endogenous neuronal modulator to quell microglial activation. Experiments with fractalkine receptor null mice suggest that fractalkine signaling diminishes tau pathology, but exacerbates amyloid pathology. Consistent with this outcome, we report here that soluble fractalkine overexpression using adeno-associated viral vectors significantly reduced tau pathology in the rTg4510 mouse model of tau deposition. Furthermore, this treatment reduced microglial activation and appeared to prevent neurodegeneration normally found in this model. However, in contrast to studies with fractalkine receptor null mice, parallel studies in an APP/PS1 model found no effect of increased fractalkine signaling on amyloid deposition. These data argue that agonism at fractalkine receptors might be an excellent target for therapeutic intervention in tauopathies, including those associated with amyloid deposition.

Tau pathology associates with several neurodegenerative diseases including Alzheimer's disease (AD) collectively known as tauopathies. The role of inflammation in neurodegenerative diseases remains controversial yet provides opportunity for therapeutic intervention. By-products of certain activation profiles reduce disease pathology whereas others promote it. Inhibiting one pathway along the inflammatory milieu may promote an alternative cascade. Arginase 1 (Arg1) and nitric oxide synthases (NOS) increase during certain disease states and have been implicated in AD pathogenesis. Arg1 and NOS compete for L-arginine to produce either ornithine and polyamines or nitric oxide, respectively. Polyamines act as bivalent regulators of cellular function, promoting cell growth or cell death, depending on cell type and the microenvironment. We identified dysregulation of proteins associated with polyamine synthesis and metabolism in rTg4510 tau transgenic mice compared to non-transgenic littermates. We postulate that increased Arg1 expression in the CNS impacts tau pathology. Four month-old rTg4510 tau transgenic mice receive an intracranial injection of recombinant adeno associated virus (rAAV) into the hippocampus of either rAAV-Arg1 or a control vector rAAV-GFP. Four months post injection brains were harvested for histology, immunohistochemistry, western blotting and ELISA. We show that overexpression Arg1 for a duration of four months in the hippocampus of rTg4510 tau transgenic mice using rAAV-Arg1 reduced several phospho-tau epitopes (i.e. AT8, AT180, AT270, Ser262, Ser396) and tangle pathology indicated by Gallyas silver positive staining compared the control vector rAAV-GFP (green fluorescent protein). Furthermore we found that Arg1 decreased several kinases associated with phospho-tau including phospho-GSK3 alpha 216/ beta 279 and CDK5 levels. Additionally, Arg1 overexpression decreased several cytokines and inflammatory markers including IL-1beta, TNF-alpha, IL-12, along with microglial activation measured by CD45 immunohistochemistry. Unbiased stereology showed no change in the number of neurons compared to the control vector however, Arg1 overexpression slightly but significantly mitigated hippocampal atrophy. These data suggests that Arg1 and the polyamine pathway may provide new and potential therapeutic targets for AD and tauopathies.