Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy.

Vascular mechanisms of Alzheimer's disease (AD) may constitute a therapeutically addressable biological pathway underlying dementia. We previously demonstrated that soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, including prominently in microvascular endothelial cells. Here we show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy and drives AD-like brain microvascular deficits. Microvascular impairments in P301S(PS19) mice were partially negated by selective removal of pathogenic soluble tau aggregates from brain. We found that similar to trans-neuronal transmission of pathogenic forms of tau, soluble tau aggregates are internalized by brain microvascular endothelial cells in a heparin-sensitive manner and induce microtubule destabilization, block endothelial nitric oxide synthase (eNOS) activation, and potently induce endothelial cell senescence that was recapitulated in vivo in microvasculature of P301S(PS19) mice. Our studies suggest that soluble pathogenic tau aggregates mediate AD-like brain microvascular deficits in a mouse model of tauopathy, which may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of soluble tau aggregates.

Brain cellular senescence in mouse models of Alzheimer's disease.

The accumulation of senescent cells contributes to aging pathologies, including neurodegenerative diseases, and its selective removal improves physiological and cognitive function in wild-type mice as well as in Alzheimer's disease (AD) models. AD models recapitulate some, but not all components of disease and do so at different rates. Whether brain cellular senescence is recapitulated in some or all AD models and whether the emergence of cellular senescence in AD mouse models occurs before or after the expected onset of AD-like cognitive deficits in these models are not yet known. The goal of this study was to identify mouse models of AD and AD-related dementias that develop measurable markers of cellular senescence in brain and thus may be useful to study the role of cellular senescence in these conditions. We measured the levels of cellular senescence markers in the brains of P301S(PS19), P301L, hTau, and 3xTg-AD mice that model amyloidopathy and/or tauopathy in AD and related dementias and in wild-type, age-matched control mice for each strain. Expression of cellular senescence markers in brains of transgenic P301L and 3xTg-AD mice was largely indistinguishable from that in WT control age-matched mice. In contrast, markers of cellular senescence were differentially increased in brains of transgenic hTau and P301S(PS19) mice as compared to WT control mice before the onset of AD-like cognitive deficits. Taken together, our data suggest that P301S(PS19) and hTau mice may be useful models for the study of brain cellular senescence in tauopathies including, but not limited to, AD.

Primary neuron and astrocyte cultures from postnatal Callithrix jacchus: a non-human primate in vitro model for research in neuroscience, nervous system aging, and neurological diseases of aging.

The ability to generate in vitro cultures of neuronal cells has been instrumental in advancing our understanding of the nervous system. Rodent models have been the principal source of brain cells used in primary cultures for over a century, providing insights that are widely applicable to human diseases. However, therapeutic agents that showed benefit in rodent models, particularly those pertaining to aging and age-associated dementias, have frequently failed in clinical trials. This discrepancy established a potential "translational gap" between human and rodent studies that may at least partially be explained by the phylogenetic distance between rodent and primate species. Several non-human primate (NHP) species, including the common marmoset (Callithrix jacchus), have been used extensively in neuroscience research, but in contrast to rodent models, practical approaches to the generation of primary cell culture systems amenable to molecular studies that can inform in vivo studies are lacking. Marmosets are a powerful model in biomedical research and particularly in studies of aging and age-associated diseases because they exhibit an aging phenotype similar to humans. Here, we report a practical method to culture primary marmoset neurons and astrocytes from brains of medically euthanized postnatal day 0 (P0) marmoset newborns that yield highly pure primary neuron and astrocyte cultures. Primary marmoset neuron and astrocyte cultures can be generated reliably to provide a powerful NHP in vitro model in neuroscience research that may enable mechanistic studies of nervous system aging and of age-related neurodegenerative disorders. Because neuron and astrocyte cultures can be used in combination with in vivo approaches in marmosets, primary marmoset neuron and astrocyte cultures may help bridge the current translational gap between basic and clinical studies in nervous system aging and age-associated neurological diseases.