Isomerase Pin1 Stimulates Dephosphorylation of Tau Protein at Cyclin-dependent Kinase (Cdk5)-dependent Alzheimer Phosphorylation Sites

Kimura, Taeko; Tsutsumi, Koji; Taoka, Masato; Saito, Taro; Masuda-Suzukake, Masami; Ishiguro, Koichi; Plattner, Florian; Uchida, Takafumi; Isobe, Toshiaki; Hasegawa, Masato; Hisanaga, Shin Ichi

doi:10.1074/jbc.m112.433326

Cited by 57 publications

(55 citation statements)

References 68 publications

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“…Among these kinases, Cdk5 is particularly interesting because it may play a crucial role in the pathogenesis of AD and regulate activity of other critical kinases including Gsk-3β. An increasing number of studies in vitro and in vivo have shown that Cdk5 has a strong relationship with the phosphorylation of tau and the progression of neurofibrillary tangles [62,63]. Cdk5 mediated-hyperphosphorylation of tau makes tau no longer connect with the microtubules but aggregates into the filaments and tangles, ultimately leading to synaptic loss and neuronal death.…”

Section: Cdk5 Mediates Tau Hyperphosphorylationmentioning

confidence: 98%

The Role of Cdk5 in Alzheimer’s Disease

et al. 2015

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Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing β-amyloid (Aβ)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.

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Section: Cdk5 Mediates Tau Hyperphosphorylationmentioning

confidence: 98%

The Role of Cdk5 in Alzheimer’s Disease

et al. 2015

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“…Most relevant to AD, Pin1-mediated isomerization drives APP cleavage toward the α and away from the β/γ secretase pathway, reducing Aβ42 production (7, 8). By binding to and isomerizing p-tau, Pin1 also prevents neurofibrillary tangle formation (4), again suggesting a possible role for its dysfunction in AD pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Pin1 mediates Aβ ₄₂ -induced dendritic spine loss

Stallings

O'Neal

et al. 2018

Sci. Signal.

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Early-stage Alzheimer’s disease is characterized by the loss of dendritic spines in the neocortex of the brain. This phenomenon precedes tau pathology, plaque formation, and neurodegeneration and likely contributes to synaptic loss, memory impairment, and behavioral changes in patients. Studies suggest that spine loss is induced by soluble, multimeric Aβ42, whose post-synaptic signaling activates the protein phosphatase calcineurin. We investigated how calcineurin causes spine pathology and found that the cis-trans prolyl isomerase Pin1 is a critical downstream target of Aβ42/calcineurin signaling. In spines, Pin1 interacts with and is dephosphorylated by calcineurin, which rapidly suppresses its isomerase activity. Pin1 knock-out or Aβ42 exposure induced mature spine loss that was prevented by exogenous Pin1. The calcinuerin inhibitor FK506 blocked spine loss in Aβ42-treated wild-type cells but had no effect on Pin1 null neurons. The data implicate Pin1 in spine maintenance and synaptic loss in early Alzheimer’s disease.

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“…In response to increases in calcium concentration, p35 is cleaved to p25 which is more stable and causes CDK5 hyper-activation; additionally, CDK5/p25 complex has changes in substrate specificity and cellular localization [160]. Abnormal CDK5 activity promotes the major AD pathology: Extracellular senile plaque and intracellular neurofibrillary tangles (NFTs) through facilitating Aβ production and tau phosphorylation [7,159,[161][162][163], and thus impairs synaptic plasticity and induces neuronal cell death [159]. Abnormal CDK5 activation leads to ROS accumulation in neuronal cells including Neuro-2a cells [164,165], suggesting a role of CDK5 dysfunction in DNA damage in neurons.…”

Section: Role Of Cdk5 Abnormalities In Ad Via Affecting Dna Damagementioning

confidence: 99%

“…AD was first described by Alois Alzheimer more than one century ago on a patient named Auguste D [1]; the typical pathological features include extensive cerebral amyloid plaques and neurofibrillary tangles [2,3]. The latter is caused by intraneuronal aggregation of hyperphosphorylated tau; abnormal tau phosphorylation is attributable to several kinases including CDK5 [4][5][6][7]. Additionally, CDK5 phosphorylates the amyloid precursor protein (APP) at threonine 668 (T668), which stimulates β-amyloid (Aβ) peptide accumulation [8].…”

Section: Introductionmentioning

confidence: 99%

Contributions of DNA Damage to Alzheimer’s Disease

Lin

Kapoor

et al. 2020

IJMS

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Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.Int. J. Mol. Sci. 2020, 21, 1666 2 of 26 amyloid (senile) plaques in AD brain [9][10][11]. Furthermore, CDK5 activities affect DNA damage response [12], supporting a linkage of DNA damage with AD [13,14].Aβ peptides are directly produced by sequential cleavages of APP by βand γ-secretase; the proteolytic c-terminal fragment of APP (CTFβ) of β-secretase is cleaved within the cell membrane by γ-secretase to generate neurotoxic Aβ peptides with length ranging from 38-43 residues [15][16][17][18][19]. The 40 residue Aβ peptide (Aβ 1-40 ) is the major product, accounting for more than 50% of Aβ peptides [9,17]. Although the Aβ 1-42 peptide consists of less than 10% of Aβ peptides [16,17], it is more neurotoxic and associates with a higher risk of AD because of its propensity of aggregation [9]. The importance of Aβ in AD pathogenesis is illustrated by mutations of APP, PSEN1, and PREN2 genes in familial AD with the latter two encoding the presenilin 1 and presenilin 2 subunit of γ-secretase. Individuals with these mutations develop early onset dementia in an autosomal-dominant manner [20]; the typical onset starts between 30 and 50 years of age in PSEN1 mutant carriers with some being affected at in their 20s [20,21]. γ-secretase with mutant presenilin 1 or presenilin 2 subunit favors Aβ 1-42 production [16,17]. These genetic observations led to formation of the amyloid cascade hypothesis, in which abnormal Aβ drives AD pathogenesis via regulating other pathological events including tau pathology [22][23][24][25][26][27]. This hypothesis is supported by the similar pathological features between familial AD and sporadic late onset AD (LOAD) [20]. Although familial AD constitutes less than 1% of AD cases [28,29], the hypothesis has been widely accepted to guide research in advancing the understanding of both familial AD and LOAD in the past two decades [30,31].Nonetheless, it is becoming in...

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Isomerase Pin1 Stimulates Dephosphorylation of Tau Protein at Cyclin-dependent Kinase (Cdk5)-dependent Alzheimer Phosphorylation Sites

Cited by 57 publications

References 68 publications

The Role of Cdk5 in Alzheimer’s Disease

The Role of Cdk5 in Alzheimer’s Disease

Pin1 mediates Aβ ₄₂ -induced dendritic spine loss

Contributions of DNA Damage to Alzheimer’s Disease

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Isomerase Pin1 Stimulates Dephosphorylation of Tau Protein at Cyclin-dependent Kinase (Cdk5)-dependent Alzheimer Phosphorylation Sites

Cited by 57 publications

References 68 publications

The Role of Cdk5 in Alzheimer’s Disease

The Role of Cdk5 in Alzheimer’s Disease

Pin1 mediates Aβ 42 -induced dendritic spine loss

Contributions of DNA Damage to Alzheimer’s Disease

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Pin1 mediates Aβ ₄₂ -induced dendritic spine loss