Tau: The Center of a Signaling Nexus in Alzheimer's Disease

Khan, Shahzad S.; Bloom, George S.

doi:10.3389/fnins.2016.00031

Cited by 98 publications

(80 citation statements)

References 63 publications

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“…Pathological tau, by contrast, exhibits altered solubility properties, forms filamentous structures, and is abnormally phosphorylated (Khan & Bloom, 2016). Hyperphosphorylated tau accumulates to form neurofibrillary tangles (NFTs), which are hallmark lesions of several neurodegenerative disorders including Alzheimer's disease (AD), frontotemporal dementia with Parkinsonism linked to chromosome 17, Pick's disease, progressive supranuclear palsy, and corticobasal degeneration (Khan & Bloom, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Hyperphosphorylated tau accumulates to form neurofibrillary tangles (NFTs), which are hallmark lesions of several neurodegenerative disorders including Alzheimer's disease (AD), frontotemporal dementia with Parkinsonism linked to chromosome 17, Pick's disease, progressive supranuclear palsy, and corticobasal degeneration (Khan & Bloom, 2016). Collectively, these disorders are known as tauopathies.…”

Section: Introductionmentioning

confidence: 99%

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Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

et al. 2018

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SummaryMisfolded and hyperphosphorylated tau accumulates in several neurodegenerative disorders including Alzheimer's disease, frontotemporal dementia with Parkinsonism, corticobasal degeneration, progressive supranuclear palsy, Down syndrome, and Pick's disease. Tau is a microtubule‐binding protein, and its role in microtubule stabilization is well defined. In contrast, while growing evidence suggests that tau is also involved in synaptic physiology, a complete assessment of tau function in the adult brain has been hampered by robust developmental compensation of other microtubule‐binding proteins in tau knockout mice. To circumvent these developmental compensations and assess the role of tau in the adult brain, we generated an adeno‐associated virus (AAV) expressing a doxycycline‐inducible short‐hairpin (Sh) RNA targeted to tau, herein referred to as AAV‐ShRNATau. We performed bilateral stereotaxic injections in 7‐month‐old C57Bl6/SJL wild‐type mice with either the AAV‐ShRNATau or a control AAV. We found that acute knockdown of tau in the adult hippocampus significantly impaired motor coordination and spatial memory. Blocking the expression of the AAV‐ShRNATau, thereby allowing tau levels to return to control levels, restored motor coordination and spatial memory. Mechanistically, the reduced tau levels were associated with lower BDNF levels, reduced levels of synaptic proteins associated with learning, and decreased spine density. We provide compelling evidence that tau is necessary for motor and cognitive function in the adult brain, thereby firmly supporting that tau loss‐of‐function may contribute to the clinical manifestations of many tauopathies. These findings have profound clinical implications given that anti‐tau therapies are in clinical trials for Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

et al. 2018

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“…Although abnormal aggregation and deposition of Aβ has attracted popular attention in the last decade as the primary causative mechanism of AD, it has been proposed that a second mechanism might play an equally important role in the pathophysiology of AD (27) via formation of neurofibrillary tangles. These tangles are insoluble fibers found within the somatodendritic and axons in AD patients (28).…”

Section: Pathophysiology Of Admentioning

confidence: 99%

Alzheimer’s Disease: Dawn of a New Era?

et al. 2017

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Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by a progressive decline in cognition and memory, leading to significant impairment in daily activities and ultimately death. It is the most common cause of dementia, the prevalence of which increases with age; however, age is not the only predisposing factor. The pathology of this cognitive impairing disease is still not completely understood, which has limited the development of valid therapeutic options. Recent years have witnessed a wide range of novel approaches to combat this disease, so that they greatly increased our understanding of the disease and of the unique drug development issues associated with this disease. In this paper, we provide a brief overview of the history, the clinical presentation and diagnosis, and we undertake a comprehensive review of the various approaches that have been brought to clinical trials in recent years, including immunotherapeutic approaches, tau-targeted strategies, neurotransmitter-based therapies, neurotropic and hematopoietic growth factors, and antioxidant therapies, trying to highlight the lessons learned from these approaches. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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“…The C-terminal domain of Tau binds to α and β-tubulin to assemble microtubules and regulates the axonal transport of neurotransmitters. In AD, an excessive kinase activity and/or a shortfall of phosphatase activity lead to Tau hyperphosphorylation 49 . Hyperphosphorylated Tau accumulates in the dendrites and cell body of the neuron, forms helical filaments and subsequently neurofibrillary tangles 50 .…”

Section: Arachidonic Acid and Taumentioning

confidence: 99%

“…Tau is a microtubule associated protein which is physiologically weakly phosphorylated and concentrated in the neuronal axons 49 ( Figure, top). The C-terminal domain of Tau binds to α and β-tubulin to assemble microtubules and regulates the axonal transport of neurotransmitters.…”

Section: Arachidonic Acid and Taumentioning

confidence: 99%

Arachidonic acid in Alzheimer's disease

Olivier¹

2016

J Neurol Neuromedicine

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Alzheimer's disease is a very complex disease in which neuroinflammation and synaptic dysfunctions play a critical role in association with the two wellknown molecular agents of the disease, the Aβ 1-42 peptide oligomers and the hyperphosphorylated tau protein. Arachidonic acid, the main member of the ω-6 series, is quantitatively the second polyunsaturated fatty acid in brain and is mainly esterified in membrane phospholipids. It is specifically released by the cytosolic phospholipase A 2 whose inhibition or gene suppression counteract the deleterious effects of Aβ 1-42 peptide oligomers on cognitive abilities. Arachidonic acid can be reincorporated under the action of the acylCoA synthetase 4 and lysophospholipid acyltransferases which remain to be characterized. Free arachidonic acid can be involved in Alzheimer's disease through several mechanisms. First it is converted by cyclooxygenases-1/2 and the specific prostaglandin synthases into PGE2 and PGD2 which contributes to the occurrence and progression of neuroinflammation. Neuroinflammation has positive as well as negative effects, by favoring Aβ 1-42 peptide clearance on one hand and by increasing the production of neurotoxic compounds on the other hand. Second, free arachidonic acid is also involved in synaptic functions as a retrograde messenger and as a regulator of neuromediator exocytosis. Third, some studies indicated that free arachidonic acid and its derivatives activate kinases involved in tau hyperphosphorylation. In addition, the dietary intakes of arachidonic acid in western food increased in the last period. Taken together, these various reports support the hypothesis that arachidonic acid is interesting target in nutrition-based preventive strategies against this disease.

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Tau: The Center of a Signaling Nexus in Alzheimer's Disease

Cited by 98 publications

References 63 publications

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

Alzheimer’s Disease: Dawn of a New Era?

Arachidonic acid in Alzheimer's disease

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