Early treatment with an M1 and sigma-1 receptor agonist prevents cognitive decline in a transgenic rat model displaying Alzheimer-like amyloid pathology.

The application of the selective allosteric M1 muscarinic and sigma-1 receptor agonist, AF710B (aka ANAVEX3-71), has shown to attenuate Alzheimer's disease-like hallmarks in McGill-R-Thy1-APP transgenic rats when administered at advanced pathological stages. It remains unknown whether preventive treatment strategies applying this compound may be equally effective. We tested whether daily oral administration of AF710B (10 µg/kg) in 7-month-old, preplaque, McGill-R-Thy1-APP rats for 7 months, followed by a 4-week washout period, could prevent Alzheimer's disease-like pathological hallmarks. Long-term AF710B treatment prevented the cognitive impairment of McGill-R-Thy1-APP rats. The effect was accompanied by a reduction in the number of amyloid plaques in the hippocampus and the levels of Aß42 and Aß40 peptides in the cerebral cortex. AF710B treatment also reduced microglia and astrocyte recruitment toward CA1 hippocampal Aß-burdened neurons compared to vehicle-treated McGill-R-Thy1-APP rats, also altering the inflammatory cytokines profile. Lastly, AF710B treatment rescued the conversion of brain-derived neurotrophic factor precursor to its mature and biologically active form. Overall, these results suggest preventive and disease-modifying properties of the compound.

Progressive human-like tauopathy with downstream neurodegeneration and neurovascular compromise in a transgenic rat model.

Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), clinically present with progressive cognitive decline and the deposition of neurofibrillary tangles (NFTs) in the brain. Neurovascular compromise is also prevalent in AD and FTD however the relationship between tau and the neurovascular unit is less understood relative to other degenerative phenotypes. Current animal models confer the ability to recapitulate aspects of the CNS tauopathies, however, existing models either display overaggressive phenotypes, or do not develop neuronal loss or genuine neurofibrillary lesions. In this report, we communicate the longitudinal characterization of brain tauopathy in a novel transgenic rat model, coded McGill-R955-hTau. The model expresses the longest isoform of human P301S tau. Homozygous R955-hTau rats displayed a robust, progressive accumulation of mutated human tau leading to the detection of tau hyperphosphorylation and cognitive deficits accelerating from 14 months of age. This model features extensive tau hyperphosphorylation with endogenous tau recruitment, authentic neurofibrillary lesions, and tau-associated neuronal loss, ventricular dilation, decreased brain volume, and gliosis in aged rats. Further, we demonstrate how neurovascular integrity becomes compromised at aged life stages using a combination of electron microscopy, injection of the tracer horseradish peroxidase and immunohistochemical approaches.