SUMMARY
Accumulation of tau is a critical event in several neurodegenerative
disorders, collectively known as tauopathies, which include Alzheimer’s
disease and frontotemporal dementia. Pathological tau is hyperphosphorylated and
aggregates to form neurofibrillary tangles. The molecular mechanisms leading to
tau accumulation remain unclear and more needs to be done to elucidate them. Age
is a major risk factor for all tauopathies, suggesting that molecular changes
contributing to the aging process may facilitate tau accumulation and represent
common mechanisms across different tauopathies. Here, we use multiple animal
models and complementary genetic and pharmacological approaches to show that the
mammalian target of rapamycin (mTOR) regulates tau phosphorylation and
degradation. Specifically, we show that genetically increasing mTOR activity
elevates endogenous mouse tau levels and phosphorylation. Complementary to it,
we further demonstrate that pharmacologically reducing mTOR signaling with
rapamycin ameliorates tau pathology and the associated behavioral deficits in a
mouse model overexpressing mutant human tau. Mechanistically, we provide
compelling evidence that the association between mTOR and tau is linked to
GSK3β and autophagy function. In summary, we show that increasing mTOR
signaling facilitates tau pathology while reducing mTOR signaling ameliorates
tau pathology. Given the overwhelming evidence showing that reducing mTOR
signaling increases lifespan and health span, the data presented here have
profound clinical implications for aging and tauopathies and provide the
molecular basis for how aging may contribute to tau pathology. Additionally,
these results provide pre-clinical data indicating that reducing mTOR signaling
may be a valid therapeutic approach for tauopathies.
Background: Accumulating evidence indicates that  receptors (AR) may be involved in Alzheimer disease (AD) pathology and that amyloid  peptide (A) may interact with  2 AR independently of presynaptic activities. Results:  2 AR, PKA, and JNK mediate A-induced phosphorylation of tau in vivo and in vitro. Conclusion: An A- 2 AR signaling is involved in tau pathology in AD. Significance: This work indicates a potential mechanism for altering AD pathology by blocking  2 ARs.
Currently, there are no available approaches to cure or slow down the progression of Alzheimer’s disease (AD), which is characterized by the accumulation of extracellular amyloid-β (Aβ) deposits and intraneuronal tangles composed of hyperphosphorylated tau. β2 adrenergic receptors (β2ARs) are expressed throughout the cortex and hippocampus and play a key role in cognitive functions. Alterations in the function of these receptors have been linked to Alzheimer’s disease; however these data remain controversial as apparent contradicting reports have been published. Given the current demographics of growing elderly population and the high likelihood of concurrent beta-blocker use for other chronic conditions, more studies into the role of this receptor in AD animal models are needed. Here we show that administration of ICI 118,551, a selective β2AR antagonist, exacerbates cognitive deficits in a mouse model of AD, the 3xTg-AD mice. Neuropathologically, ICI 118,551 increased Aβ levels and Aβ plaque burden. Concomitantly, ICI 118,551-treated 3xTg-AD mice showed an increase in tau phosphorylation and accumulation. Mechanistically, these changes were linked to an increase in amyloidogenic APP processing. These results suggest that under the conditions used here, selective pharmacological inhibition of β2ARs has detrimental effects on AD-like pathology in mice. Overall, these studies strengthen the notion that the link between β2ARs and AD is likely highly complex and suggest caution in generalizing the beneficial effects of beta-blockers on AD.
Accumulation of the microtubule-binding protein tau is a key event in several neurodegenerative disorders referred to as tauopathies, which include Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. Thus, understanding the molecular pathways leading to tau accumulation will have a major impact across multiple neurodegenerative disorders. To elucidate the pathways involved in tau pathology, we removed the gene encoding the beta-2 adrenergic receptors (β2ARs) from a mouse model overexpressing mutant human tau. Notably, the number of β2ARs is increased in brains of AD patients and epidemiological studies show that the use of beta-blockers decreases the incidence of AD. The mechanisms underlying these observations, however, are not clear. We show that the tau transgenic mice lacking the β2AR gene had a reduced mortality rate compared with the parental tau transgenic mice. Removing the gene encoding the β2ARs from the tau transgenic mice also significantly improved motor deficits. Neuropathologically, the improvement in lifespan and motor function was associated with a reduction in brain tau immunoreactivity and phosphorylation. Mechanistically, we provide compelling evidence that the β2AR-mediated changes in tau were linked to a reduction in the activity of GSK3β and CDK5, two of the major tau kinases. These studies provide a mechanistic link between β2ARs and tau and suggest the molecular basis linking the use of beta-blockers to a reduced incidence of AD. Furthermore, these data suggest that a detailed pharmacological modulation of β2ARs could be exploited to develop better therapeutic strategies for AD and other tauopathies.
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