The Co-chaperone BAG2 Mediates Cold-Induced Accumulation of Phosphorylated Tau in SH-SY5Y Cells.

Inclusions of phosphorylated tau (p-tau) are a hallmark of many neurodegenerative disorders classified as "tauopathy," of which Alzheimer's disease is the most prevalent form. Dysregulation of tau phosphorylation disrupts neuron structure and function, and hyperphosphorylated tau aggregates to form neurotoxic inclusions. The abundance of ubiquitin in tau inclusions suggests a defect in ubiquitin-mediated tau protein degradation by the proteasome. Under the temperature of 37 °C, the co-chaperone BAG2 protein targets phosphorylated tau for degradation via by a more-efficient, ubiquitin-independent pathway. In both in vivo and in vitro studies, cold exposure induces the accumulation of phosphorylated tau protein. The SH-SY5Y cell line differentiates into neuron-like cells on treatment with retinoic acid and is an established model for research on the effects of cold on tau phosphorylation. The aim of the present study was to investigate whether BAG2 mediates the cold-induced accumulation of phosphorylated tau protein. Our findings show that cold exposure causes a decrease in BAG2 expression in undifferentiated cells. Conversely, BAG2 expression is increased in differentiated cells exposed to cold. Further, undifferentiated cells exposed to cold had an increased proportion of p-tau to total tau, suggesting an accumulation of p-tau that is consistent with decreased levels of BAG2. Overexpression of BAG2 in cold-exposed undifferentiated cells restored levels of p-tau to those of 37 °C undifferentiated control. Interestingly, although BAG2 expression increased in differentiated cells, this increase was not accompanied by a decrease in the proportion of p-tau to total tau. Further, overexpression of BAG2 in cold exposed differentiated cells showed no significant difference in p-tau levels compared to 37 °C controls. Taken together, these data show that expression of BAG2 is differently regulated in a differentiation-dependent context. Our results suggest that repression of BAG2 expression or BAG2 activity by cold-sensitive pathways, as modeled in undifferentiated and differentiated cells, respectively, may be a causal factor in the accumulation of cytotoxic hyperphosphorylated tau protein via restriction of BAG2-mediated clearance of cellular p-tau.

BAG2 expression dictates a functional intracellular switch between the p38-dependent effects of nicotine on tau phosphorylation levels via the α7 nicotinic receptor.

The histopathological hallmarks present in Alzheimer's disease (AD) brain are plaques of Aß peptide, neurofibrillary tangles of hyperphosphorylated tau protein, and a reduction in nicotinic acetylcholine receptor (nAChR) levels. The role of nAChRs in AD is particularly controversial. Tau protein function is regulated by phosphorylation, and its hyperphosphorylated forms are significantly more abundant in AD brain. Little is known about the relationship between nAChR and phospho-tau degradation machinery. Activation of nAChRs has been reported to increase and decrease tau phosphorylation levels, and the mechanisms responsible for this discrepancy are not presently understood. The co-chaperone BAG2 is capable of regulating phospho-tau levels via protein degradation. In SH-SY5Y cell line and rat primary hippocampal cell culture low endogenous BAG2 levels constitute an intracellular environment conducive to nicotine-induced accumulation of phosphorylated tau protein. Further, nicotine treatment inhibited endogenous expression of BAG2, resulting in increased levels of phosphorylated tau indistinguishable from those induced by BAG2 knockdown. Conversely, overexpression of BAG2 is conducive to a nicotine-induced reduction in cellular levels of phosphorylated tau protein. In both cases the effect of nicotine was p38MAPK-dependent, while the α7 antagonist MLA was synthetic to nicotine treatment, either increasing levels of phospho-Tau in the absence of BAG2, or further decreasing the levels of phospho-Tau in the presence of BAG2. Taken together, these findings reconcile the apparently contradictory effects of nicotine on tau phosphorylation by suggesting a role for BAG2 as an important regulator of p38-dependent tau kinase activity and phospho-tau degradation in response to nicotinic receptor stimulation. Thus, we report that BAG2 expression dictates a functional intracellular switch between the p38-dependent functions of nicotine on tau phosphorylation levels via the α7 nicotinic receptor.

Temperature and toxic Tau in Alzheimer's disease: new insights.

Alzheimer's disease (AD), the most common dementia in the elderly, is characterized by cognitive impairment and severe autonomic symptoms such as disturbance in core body temperature (Tc), which may be predictors or early events in AD onset. Inclusions of phosphorylated Tau (p-Tau) are a hallmark of AD and other neurodegenerative disorders called "Tauopathies." Animal and human studies show that anesthesia augments p-Tau levels through reduction of Tc, with implications for AD. Additionally, hypothermia impairs memory and cognitive function. The molecular networks related to Tc that are associated with AD remain poorly characterized. Under physiological conditions, Tau binds microtubules, promoting their assembly and stability. The dynamically regulated Tau-microtubule interaction plays an important role in structural remodeling of the cytoskeleton, having important functions in neuronal plasticity and memory in the hippocampus. Hypothermia-induced increases in p-Tau levels are significant, with an 80% increase for each degree Celsius below normothermic conditions. Although the effects of temperature on Tau phosphorylation are evident, its effects on p-Tau degradation remain poorly understoodWe review information concerning the mechanisms of Tau regulation of neuron plasticity via its effects on microtubule dynamics, with focus on pathways regulating the abundance of phosphorylated Tau species.  We highlight the effects of temperature on molecular mechanisms influencing the development of Tau-related diseases. Specifically, we argue that cold might preferentially affects central nervous system structures that are highly reliant upon plasticity, such as the hippocampus, and that the effect of cold on Tau phosphorylation may constitute a pathology-initiating trigger leading to neurodegeneration.