APP processing is regulated by cytoplasmic phosphorylation

Lee, Ming Sum; Kao, Shih Chu; Lemere, Cynthia A.; Xia, Weiming; Tseng, Huang Chun; Zhou, Ying; Neve, Rachael L.; Ahlijanian, Michael K.; Tsai, Li Huei

doi:10.1083/jcb.200301115

Cited by 398 publications

(407 citation statements)

References 45 publications

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“…Subsequently, CTFα and CTFβ are then cleaved by γ‐secretase, producing p3 and Aβ peptides, respectively, and AICD (the APP intracellular domain). In addition to protease cleavage, phosphorylation of APP on Thr668 site facilitates the generation of Aβ (Lee et al ., 2003). Therefore, we investigated the above APP processing products and the phosphorylation of APP on Thr668 in the hippocampus of APP/PS1 mice.…”

Section: Resultsmentioning

confidence: 99%

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

et al. 2016

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SummaryBrain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β‐amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5‐month‐old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c‐Jun N‐terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Aβ metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aβ pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.

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Section: Resultsmentioning

confidence: 99%

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

et al. 2016

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“…35−37 CDK5 (cyclin-dependent kinase-5) and GSK-3β (glycogen synthase kinase-3β) are thought to phosphorylate APP at Thr 668 in neurons 38−40 and when cells are subjected to a stress stimulus, c-Jun N-terminal kinase (JNK) may also phosphorylate APP at Thr 668 . 41,42 Hyperphosphorylation of APP in AD patients' brain may also be explained by the Aβ inhibition of phosphoprotein phosphatase 1 (PPP1) 35 or PPP2, thus contributing to the phosphorylation of APP at Thr668. 43 As already referred, another hallmark in AD is the hyperphosphorylation of tau protein (Figure 1), and phosphorylation of tau regulates its binding activity to microtubules stimulating their assembly.…”

Section: ■ Kinases and Phosphatases: Involvement In Alzheimer's Diseasementioning

confidence: 99%

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Baptista

Henriques

Silva

et al. 2014

ACS Chem. Neurosci.

161

111

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Alzheimer's disease is characterized by pathological aggregation of protein tau and amyloid-β peptides, both of which are considered to be toxic to neurons. Naturally occurring dietary flavonoids have received considerable attention as alternative candidates for Alzheimer's therapy taking into account their antiamyloidogenic, antioxidative, and anti-inflammatory properties. Experimental evidence supports the hypothesis that certain flavonoids may protect against Alzheimer's disease in part by interfering with the generation and assembly of amyloid-β peptides into neurotoxic oligomeric aggregates and also by reducing tau aggregation. Several mechanisms have been proposed for the ability of flavonoids to prevent the onset or to slow the progression of the disease. Some mechanisms include their interaction with important signaling pathways in the brain like the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways that regulate prosurvival transcription factors and gene expression. Other processes include the disruption of amyloid-β aggregation and alterations in amyloid precursor protein processing through the inhibition of β-secretase and/or activation of α-secretase, and inhibiting cyclin-dependent kinase-5 and glycogen synthase kinase-3β activation, preventing abnormal tau phosphorylation. The interaction of flavonoids with different signaling pathways put forward their therapeutic potential to prevent the onset and progression of Alzheimer's disease and to promote cognitive performance. Nevertheless, further studies are needed to give additional insight into the specific mechanisms by which flavonoids exert their potential neuroprotective actions in the brain of Alzheimer's disease patients. KEYWORDS: Flavonoids, Alzheimer's disease, amyloid precursor protein, amyloid beta, BACE-1, tau, signaling A lzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia worldwide. The major histopathological hallmarks of AD include proteinous aggregates in the form of neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau 1,2 and extracellular senile plaques, which are deposits of heterogeneously sized small peptides of amyloid-β (Aβ) that are formed via sequential proteolytic cleavages of the amyloid precursor protein (APP) 3 (Figure 1). Dominant mutations in APP, presenilin-1 (PS1) or PS2 are responsible for the early onset or familial form of AD. These mutations have been shown to profoundly alter APP metabolism, favoring the production of aggregation-prone Aβ species, these findings formed the basis for the "amyloid cascade hypothesis" of AD pathogenesis. This broadly accepted hypothesis states that the generation of neurotoxic Aβ peptides by β-secretase and γ-secretase are at the basis of AD pathophysiology. Other hallmarks of this disease, like neurotransmitter changes 4,5 and neuronal and synapse loss in the neocortex and the hippocampus 6,7 develop as a consequence of this event.■ AMYLOID PRECURSOR PROTEIN APP belongs to a protein f...

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“…A possible mechanism that has been proposed to account for the interplay between DYRK1A and APP is a positive feedback loop (see Cardenas et al, 2012) in which DYRK1A phosphorylates APP at Thr668 (Ryoo et al, 2008) favoring the amyloidogenic cleavage of APP (Judge et al, 2011;Lee et al, 2003), and Aβ42 induces an upregulation of DYRK1A (Kimura et al, 2007). The cooperative effects of these genes could affect tau expression and phosphorylation and result in abnormal expression and hyperphosphorylation, favouring tau aggregation and the destabilization of microtubules.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…DYRK1A phosphorylates APP at Thr668 in vitro in cells of a mouse model that overexpresses the human DYRK1A gene (hBACtgDyrk1A) (Ryoo et al, 2008). This phosphorylation facilitates the excision of APP by β-secretase 1 (Beta-secretase 1, BACE1) and γ-secretase, inducing an accumulation of the neurotoxic peptides Aβ40 and Aβ42 (Wegiel et al, 2011;Vingtdeux et al, 2005;Lee et al, 2003). Therefore, overexpression of DYRK1A hyperphosphorylates APP leading to a cascade of Aβ accumulation.…”

Section: Introductionmentioning

confidence: 99%

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

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APP processing is regulated by cytoplasmic phosphorylation

Cited by 398 publications

References 45 publications

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

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