Tau in MAPK Activation

Leugers, Chad J.; Koh, Ju Yong; Hong, Willis; Lee, Gloria

doi:10.3389/fneur.2013.00161

Cited by 30 publications

(20 citation statements)

References 40 publications

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“…This is consistent with previous literature that alterations in tau phosphorylation are a necessary component of NGF-induced neurite outgrowth and proliferation via MAPK signaling (Leugers, et al, 2013; Leugers and Lee, 2010), suggesting a role for the phosphorylation to contribute to the reductions in adult neurogenesis. However, the particular signaling cascades are unknown.…”

Section: Discussionsupporting

confidence: 93%

Human tau expression reduces adult neurogenesis in a mouse model of tauopathy

Komuro

Bhaskar

et al. 2015

Neurobiology of Aging

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Accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) is a central feature of a class of neurodegenerative diseases termed tauopathies. Notably, there is increasing evidence that tauopathies, including Alzheimer's disease, are also characterized by a reduction in neurogenesis, the birth of adult neurons. However, the exact relationship between hyperphosphorylation and aggregation of MAPT and neurogenic deficits remains unclear, including whether this is an early- or late-stage disease marker. In the current study, we utilized the genomic –based hTau mouse model of tauopathy to examine the temporal and spatial regulation of adult neurogenesis during the course of disease. Surprisingly, hTau mice exhibited reductions in adult neurogenesis in two different brain regions by as early as 2 months of age, prior to the development of robust MAPT pathology in this model. This reduction was found to be due to reduced proliferation and not enhanced apoptosis in the hippocampus. At these same time points, hTau mice also exhibited altered MAPT phosphorylation with neurogenic precursors. To examine whether the effects of MAPT on neurogenesis were cell autonomous, neurospheres prepared from hTau animals were examined in vitro, revealing a growth deficit when compared to nontransgenic neurosphere cultures. Taken together, these studies provide evidence that altered adult neurogenesis is a robust and early marker of altered, cell-autonomous function of MAPT in the hTau mouse mode of tauopathy and that altered adult neurogenesis should be examined as a potential marker and therapeutic target for human tauopathies.

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Section: Discussionsupporting

confidence: 93%

Human tau expression reduces adult neurogenesis in a mouse model of tauopathy

Komuro

Bhaskar

et al. 2015

Neurobiology of Aging

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“…Should a reduction in pS214‐tau density signal a loss‐of‐function event, its absence from the subsynaptic domain may be particularly important to synaptic stability mechanisms. Specifically, tau within the subsynaptic domain is both strategically positioned to directly bind the actin cytoskeleton, and to participate in intracellular signaling cascades critical for actin remodeling, for example, the MAPK pathway (Cabrales Fontela et al, ; Frandemiche et al, ; He et al, ; Leugers, Koh, Hong, & Lee, ; Yamauchi & Purich, ). Notably, the interaction between tau and actin leads to accumulation of actin within mouse cortical neuron synapses (Frandemiche et al, ).…”

Section: Discussionmentioning

confidence: 99%

Synaptic distributions of pS214‐tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline

Crimins

Puri

Calakos

et al. 2018

J of Comparative Neurology

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Female rhesus monkeys and women are subject to age‐ and menopause‐related deficits in working memory, an executive function mediated by the dorsolateral prefrontal cortex (dlPFC). Long‐term cyclic administration of 17β‐estradiol improves working memory, and restores highly plastic axospinous synapses within layer III dlPFC of aged ovariectomized monkeys. In this study, we tested the hypothesis that synaptic distributions of tau protein phosphorylated at serine 214 (pS214‐tau) are altered with age or estradiol treatment, and couple to working memory performance. First, ovariectormized young and aged monkeys received vehicle or estradiol treatment, and were tested on the delayed response (DR) test of working memory. Serial section electron microscopic immunocytochemistry was then performed to quantitatively assess the subcellular synaptic distributions of pS214‐tau. Overall, the majority of synapses contained pS214‐tau immunogold particles, which were predominantly localized to the cytoplasm of axon terminals. pS214‐tau was also abundant within synaptic and cytoplasmic domains of dendritic spines. The density of pS214‐tau immunogold within the active zone, cytoplasmic, and plasmalemmal domains of axon terminals, and subjacent to the postsynaptic density within the subsynaptic domains of dendritic spines, were each reduced with age. None of the variables examined were directly linked to cognitive status, but a high density of pS214‐tau immunogold particles within presynaptic cytoplasmic and plasmalemmal domains, and within postsynaptic subsynaptic and plasmalemmal domains, accompanied high synapse density. Together, these data support a possible physiological, rather than pathological, role for pS214‐tau in the modulation of synaptic morphology in monkey dlPFC.

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“…Compelling evidence that reactivation of the cell cycle induces tau phosphorylation is provided by two studies: McShea and colleagues [55] demonstrate that cell cycle induction in vitro induces tau phosphorylation, while Park and colleagues [54] demonstrate that cell cycle induction in vivo induces NFT and amyloid deposits. More recently, it has been demonstrated that specific phosphorylation of tau (Thr231) can promote MAPK activation in PC12 cells, which in turn could (further) activate the cell cycle reentry mechanisms in neurons [127, 128]. …”

Section: Evidence That the Differential Regulation Of Aβpp Processingmentioning

confidence: 99%

A Unified Hypothesis of Early- and Late-Onset Alzheimer’s Disease Pathogenesis

Atwood

Bowen

2015

JAD

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Early-onset familial Alzheimer’s disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition (Aβ), and the deposition of phosphorylated tau protein in the form of intracellular neurofibrillary tangles in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease. Cell cycle abnormalities represent another major biochemical and neuropathological feature common to both EOFAD and LOSAD, and 1) appear very early in the disease process, prior to the appearance of plaques and tangles, and 2) explain the biochemical (e.g., tau phosphorylation), neuropathological (e.g., neuron hypertrophy) and cognitive changes observed in EOFAD and LOSAD. Since neurogenesis after the formation of a memory is sufficient to induce forgetting, any stimulus that promotes cell cycle re-entry will be a negative event for memory. In this insight paper, we propose that aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell cycle is a common pathway that explains both early and late-onset forms of AD. In the case of EOFAD, mutations in APP, PSEN1, and PSEN2 that alter AβPP and Notch processing drive reactivation of the cell cycle, while in LOSAD, age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling, AβPP processing toward the amyloidogenic pathway and tau phosphorylation drives reactivation of the cell cycle. Inhibition of cell cycle reentry of post-mitotic neurons may be a useful therapeutic strategy to prevent or halt disease progression.

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Tau in MAPK Activation

Cited by 30 publications

References 40 publications

Human tau expression reduces adult neurogenesis in a mouse model of tauopathy

Human tau expression reduces adult neurogenesis in a mouse model of tauopathy

Synaptic distributions of pS214‐tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline

A Unified Hypothesis of Early- and Late-Onset Alzheimer’s Disease Pathogenesis

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