Role of Cdk5 in Amyloid-beta Pathology of Alzheimer’s Disease

Lu, Tao; Wan, Chengqun; Yang, Weiren; Cai, Zhiyou

doi:10.2174/1567205016666191210094435

Cited by 22 publications

(10 citation statements)

References 82 publications

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“…Cyclin-dependent kinase 5 (CDK5) as a unique member of the cyclin-dependent kinase families plays an important role on regulating pathophysiological features in AD pathogenesis (Lu et al, 2020). When AD occurs, the activity of CDK5 in neuron becomes abnormally active, inducing abnormal tau hyperphosphorylation and accelerating their aggregation into filaments or tangles, eventually leading to synaptic loss and neuronal death (Shen et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles

et al. 2020

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Section: Introductionmentioning

confidence: 99%

Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles

et al. 2020

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“…Indeed, it is inhibited when phosphorylated at Ser9, which stimulates its glucose synthesis-related physiological effects [ 5 ]. Under pathological conditions, CDK5 becomes hyperactive and causes aberrant hyperphosphorylation of tau proteins in NFTs [ 6 ] and interferes with the proteolytic processing of APP, modulating Aβ by affecting the secretases, which are critical for the hydrolysis of APP [ 7 ]. Therefore, these enzymes play major roles in AD by affecting amyloid processing and NFTs formation.…”

Section: Introductionmentioning

confidence: 99%

Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer’s Disease Hallmarks in SAMP8 Mice

et al. 2021

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Alzheimer’s disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3β (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPβ, and the concentration of Aβ40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-β expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice.

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“…Interestingly, in the present study, recombinant VEGF directly prevented Aβ-mediated Cdk5 inhibition, promoted endothelial cell proliferation in bEnd.3 cells, and prevented brain capillary loss in an AD mouse model. CDK5, a member of the cyclin-dependent kinase family, regulates endothelial cell proliferation, migration, and angiogenesis, and is involved in the major pathological features of AD [54][55][56][57] . In our study, endothelial Cdk5 overexpression inhibited CXCL1 secretion and peripheral neutrophil in ltration into the AD brain.…”

Section: Discussionmentioning

confidence: 99%

Young serum protects against memory impairment in APP/PS1 transgenic mice by blocking neutrophil infiltration

Ke¹,

Zuo

et al. 2022

Preprint

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Activation of innate immunity in the brain is a prominent feature of Alzheimer's disease (AD). The present study investigated the regulation of innate immunity by young serum in a transgenic AD mouse model. We found that young serum significantly reduced the number of neutrophils and microglial reactivity in the brains of APP/PS1 mice. Neutrophil depletion via Ly6G neutralizing antibodies mimicked the benefits of young serum on AD brain functions. Serum proteomic analysis of young serum revealed significant enrichment of the factors VEGF-A and CXCL1, which are crucial for neutrophil migration and chemotaxis, leukocyte migration, and cell chemotaxis. Intravenously injected VEGF-A reversed Aβ-induced decreases in Cdk5 and increases in CXCL1 in vitro and blocked neutrophil infiltration into the AD brain. Endothelial Cdk5 overexpression conferred an inhibitory effect on CXCL1 and neutrophil infiltration and thereby restored memory in APP/PS1 mice. Our data uncover a previously unknown link between blood-derived VEGF signaling and neutrophil infiltration and provide a rationale for targeting endothelial Cdk5 signaling as a potential therapeutic strategy for AD.

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Role of Cdk5 in Amyloid-beta Pathology of Alzheimer’s Disease

Cited by 22 publications

References 82 publications

Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles

Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles

Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer’s Disease Hallmarks in SAMP8 Mice

Young serum protects against memory impairment in APP/PS1 transgenic mice by blocking neutrophil infiltration

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