A unique tau conformation generated by an acetylation-mimic substitution modulates P301S-dependent tau pathology and hyperphosphorylation.

Abnormal intracellular accumulation of aggregated tau is a hallmark feature of Alzheimer's disease and other tauopathies. Pathological tau can undergo a range of post-translational modifications (PTMs) that are implicated as triggers of disease pathology. Recent studies now indicate that tau acetylation, in particular, controls both microtubule binding and tau aggregation, thereby acting as a central regulator of tau's biochemical properties and providing avenues to exploit for potential therapies. Here, using cell-based assays and tau transgenic mice harboring an acetylation-mimic mutation at residue Lys-280 (K280Q), we evaluated whether this substitution modifies the neurodegenerative disease pathology associated with the aggregate-prone tau P301S variant. Strikingly, the addition of a K280Q-substituted variant altered P301S-mediated tau conformation and reduced tau hyperphosphorylation. We further evaluated neurodegeneration markers in K280Q acetylation-mimic mice and observed reduced neuroinflammation as well as restored levels of N-methyl-d-aspartate receptors and post-synaptic markers compared with the parental mice. Thus, substituting a single lysine residue in the context of a P301S disease-linked mutation produces a unique tau species that abrogates some of the cardinal features of tauopathy. The findings of our study indicate that a complex tau PTM code likely regulates tau pathogenesis, highlighting the potential utility of manipulating and detoxifying tau strains through site-specific tau-targeting approaches.

Distinct phenotypes of three-repeat and four-repeat human tau in a transgenic model of tauopathy.

Tau exists as six closely related protein isoforms in the adult human brain. These are generated from alternative splicing of a single mRNA transcript and they differ in the absence or presence of two N-terminal and three or four microtubule binding domains. Typically all six isoforms have been considered functionally similar. However, their differential involvement in particular tauopathies raises the possibility that there may be isoform-specific differences in physiological function and pathological role. To explore this, we have compared the phenotypes induced by the 0N3R and 0N4R isoforms in Drosophila. Expression of the 3R isoform causes more profound axonal transport defects and locomotor impairments, culminating in a shorter lifespan than the 4R isoform. In contrast, the 4R isoform leads to greater neurodegeneration and impairments in learning and memory. Furthermore, the phosphorylation patterns of the two isoforms are distinct, as is their ability to induce oxidative stress. These differences are not consequent to different expression levels and are suggestive of bona fide physiological differences in isoform biology and pathological potential. They may therefore explain isoform-specific mechanisms of tau-toxicity and the differential susceptibility of brain regions to different tauopathies.

Genetic suppression of ß2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies.

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 (ß2ARs) from a mouse model overexpressing mutant human tau. Notably, the number of ß2ARs 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 ß2AR gene had a reduced mortality rate compared with the parental tau transgenic mice. Removing the gene encoding the ß2ARs 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 ß2AR-mediated changes in tau were linked to a reduction in the activity of GSK3ß and CDK5, two of the major tau kinases. These studies provide a mechanistic link between ß2ARs 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 ß2ARs could be exploited to develop better therapeutic strategies for AD and other tauopathies.

CX3CR1-deficient microglia shows impaired signalling of the transcription factor NRF2: Implications in tauopathies.

TAU protein aggregation is the main characteristic of neurodegenerative diseases known as tauopathies. Low-grade chronic inflammation is also another hallmark that indicates crosstalk between damaged neurons and glial cells. Previously, we have demonstrated that neurons overexpressing TAUP301L release CX3CL1, which activates the transcription factor NRF2 signalling to limit over-activation in microglial cells in vitro and in vivo. However, the connection between CX3CL1/CX3CR1 and NRF2 system and its functional implications in microglia are poorly described. We evaluated CX3CR1/NRF2 axis in the context of tauopathies and its implication in neuroinflammation. Regarding the molecular mechanisms that connect CX3CL1/CX3CR1 and NRF2 systems, we observed that in primary microglia from Cx3cr1-/- mice the mRNA levels of Nrf2 and its related genes were significantly decreased, establishing a direct linking between both systems. To determine functional relevance of CX3CR1, migration and phagocytosis assays were evaluated. CX3CR1-deficient microglia showed impaired cell migration and deficiency of phagocytosis, as previously described for NRF2-deficient microglia, reinforcing the idea of the relevance of the CX3CL1/CX3CR1 axis in these events. The importance of these findings was evident in a tauopathy mouse model where the effects of sulforaphane (SFN), an NRF2 inducer, were examined on neuroinflammation in Cx3cr1+/+ and Cx3cr1-/- mice. Interestingly, the treatment with SFN was able to modulate astrogliosis but failed to reduce microgliosis in Cx3cr1-/- mice. These findings suggest an essential role of the CX3CR1/NRF2 axis in microglial function and in tauopathies. Therefore, polymorphisms with loss of function in CX3CR1 or NRF2 have to be taken into account for the development of therapeutic strategies.

Factors associated with survival probability in autopsy-proven frontotemporal lobar degeneration.

OBJECTIVE: To examine the clinical and pathological factors associated with survival in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: The final analysis cohort included 71 patients with pathologically proven FTLD, excluding patients with clinical motor neuron disease (MND), evaluated at the University of Pennsylvania or at the University of California, San Francisco. We assessed clinical and demographic features; cognitive functioning at presentation; genetic markers of disease; and graded anatomical distribution of tau, ubiquitin and amyloid pathology. RESULTS: The tau-negative group (n = 35) had a median survival time of 96 months (95% CI: 72-114 months), whereas the tau-positive group (n = 36) had a median survival time of 72 months (95% CI: 60-84 months). Patients with tau-positive pathology across all brain regions had shorter survival than those with tau-negative pathology in univariate Cox regression analyses (Hazard ratio of dying = 2.003, 95% CI = 1.209-3.318, p = 0.007). CONCLUSIONS: Tau-positive pathology represents a significant risk to survival in FTLD, whereas tau-negative pathology is associated with a longer survival time when clinical MND is excluded.

Rapidly progressive neurodegenerative dementias.

BACKGROUND: Neurodegenerative dementias are typically characterized by an insidious onset and a relatively slowly progressive course. Less common are patients with a rapidly progressive course to death. OBJECTIVE: To characterize patients with a neurodegenerative disease and a rapidly progressive course to death. DESIGN, SETTING, AND PATIENTS: Using a text word search for "rapid" and "dementia" in the same sentence, the Mayo Clinic Medical Records Linkage system was used to identify all patients evaluated between January 1, 2000, and September 30, 2007, with brain autopsy (N = 96) at a tertiary care medical center. Of these 96 patients, we included only those with disease duration of less than 4 years to death and with histological diagnosis of a neurodegenerative disease. MAIN OUTCOME MEASURES: Rapidly progressive dementia with death sooner than 4 years after onset and pathological diagnosis at our institution of a neurodegenerative disease. RESULTS: We included 22 patients (10 men). Although 8 cases (36%) had Creutzfeldt-Jakob disease (CJD), the rest had frontotemporal lobar degeneration with motor neuron degeneration (5 cases [23%]), a tauopathy (progressive supranuclear palsy or corticobasal degeneration) (4 cases [18%]), diffuse Lewy body disease (3 cases [14%]), or Alzheimer disease (2 cases [9%]). All of the patients with CJD died 12 months or sooner after onset, whereas the others had an illness duration longer than 12 months. Notably, all of the 3 patients with diffuse Lewy body disease but no others initially experienced a transient postoperative or illness-associated encephalopathy, then relative normality for 2 years, and finally a rapidly progressive dementia and decline to death in 4 to 12 months. CONCLUSIONS: Based on this cohort, although CJD is the most likely cause of a rapidly progressive neurodegenerative dementia, frontotemporal lobar degeneration with motor neuron degeneration, diffuse Lewy body disease, tauopathies, and Alzheimer disease can also cause a rapidly progressive dementia. If illness duration is beyond 12 months, a non-CJD neurodegenerative disease may be more likely than CJD to be the diagnosis.

Clinical features and survival of 3R and 4R tauopathies presenting as behavioral variant frontotemporal dementia.

We compared the clinical characteristics of 3 repeat (3R) and 4 repeat (4R) tau-positive cases (tauopathies) presenting as behavior variant frontotemporal dementia (bv-FTD). We identified and retrospectively reviewed demographics and clinical features of patients with pathologically confirmed tau-positive frontotemporal lobar degeneration in a blinded fashion. Those presenting as bv-FTD were divided according to their tau isoform, 3R versus 4R, and compared with age-matched and sex-matched control patients with 4R tauopathies but presenting clinical syndromes other than bv-FTD. Twenty-four cases with tau-positive bv-FTD and 18 4R tau-positive controls were included in the study. Patients with 4R tauopathies had significantly shorter disease duration than patients with 3R tauopathy (median, 6.5 y vs. 9.5 y; P<0.05), despite similar age of disease onset and regardless of whether bv-FTD was the presenting clinical syndrome. Among bv-FTD cases, those with 4R tauopathies were more likely to display behavioral underactivity than those with 3R tauopathy (P=0.03), although 3R and 4R tauopathy patients shared many similar clinical features. In summary, survival in 4R tauopathies seemed independent of the presenting clinical phenotype, and there may be subtle clinical differences between bv-FTD patients with 3R and 4R tauopathies.