Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer's disease (original) (raw)
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Overexpression of Kinesin Superfamily Motor Proteins in Alzheimer's Disease
Journal of Alzheimer's disease : JAD, 2017
Defects in motor protein-mediated neuronal transport mechanisms have been implicated in a number of neurodegenerative disorders but remain relatively little studied in Alzheimer's disease (AD). Our aim in the present study was to assess the expression of the anterograde kinesin superfamily motor proteins KIF5A, KIF1B, and KIF21B, and to examine their relationship to levels of hyperphosphorylated tau, amyloid-β protein precursor (AβPP), and amyloid-β (Aβ) in human brain tissue. We used a combination of qPCR, immunoblotting, and ELISA to perform these analyses in midfrontal cortex from 49 AD and 46 control brains. Expression of KIF5A, KIF1B, and KIF21B at gene and protein level was significantly increased in AD. KIF5A protein expression correlated inversely with the levels of AβPP and soluble Aβ in AD brains. Upregulation of KIFs may be an adaptive response to impaired axonal transport in AD.
Alzheimer's Presenilin 1 Mutations Impair Kinesin-Based Axonal Transport
2003
Several lines of evidence indicate that alterations in axonal transport play a critical role in Alzheimer's disease (AD) neuropathology, but the molecular mechanisms that control this process are not understood fully. Recent work indicates that presenilin 1 (PS1) interacts with glycogen synthase kinase 3 (GSK3). In vivo, GSK3 phosphorylates kinesin light chains (KLC) and causes the release of kinesin-I from membrane-bound organelles (MBOs), leading to a reduction in kinesin-I driven motility (Morfini et al., 2002b). To characterize a potential role for PS1 in the regulation of kinesin-based axonal transport, we used PS1 Ϫ/Ϫ and PS1 knock-in M146V (KI M146V ) mice and cultured cells. We show that relative levels of GSK3 activity were increased in cells either in the presence of mutant PS1 or in the absence of PS1 (PS1 Ϫ/Ϫ ). Concomitant with increased GSK3 activity, relative levels of KLC phosphorylation were increased, and the amount of kinesin-I bound to MBOs was reduced. Consistent with a deficit in kinesin-I-mediated fast axonal transport, densities of synaptophysinand syntaxin-I-containing vesicles and mitochondria were reduced in neuritic processes of KI M146V hippocampal neurons. Similarly, we found reduced levels of PS1, amyloid precursor protein, and synaptophysin in sciatic nerves of KI M146V mice. Thus PS1 appears to modulate GSK3 activity and the release of kinesin-I from MBOs at sites of vesicle delivery and membrane insertion. These findings suggest that mutations in PS1 may compromise neuronal function by affecting GSK-3 activity and kinesin-I-based motility.
Axonal Transport, Amyloid Precursor Protein, Kinesin-1, and the Processing Apparatus: Revisited
The Journal of Neuroscience, 2005
The sequential enzymatic actions of β-APP cleaving enzyme 1 (BACE1), presenilins (PS), and other proteins of the γ-secretase complex liberate β-amyloid (Aβ) peptides from larger integral membrane proteins, termed β-amyloid precursor proteins (APPs). Relatively little is known about the normal function(s) of APP or the neuronal compartment(s) in which APP undergoes proteolytic processing. Recent studies have been interpreted as consistent with the idea that APP serves as a kinesin-1 cargo receptor and that PS and BACE1 are associated with the APP-resident membranous cargos that undergo rapid axonal transport. In this report, derived from a collaboration among several independent laboratories, we examined the potential associations of APP and kinesin-1 using glutathioneS-transferase pull-down and coimmunoprecipitation assays. In addition, we assessed the trafficking of membrane proteins in the sciatic nerves of transgenic mice with heterozygous or homozygous deletions ofAPP. In contra...
Journal of neurochemistry, 2007
Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that can regulate microtubule assembly in neurons. This function of CRMP2 is regulated by phosphorylation by glycogen synthase kinase 3 (GSK3) and cyclin-dependent kinase 5 (Cdk5). Here, using novel phosphospecific antibodies, we demonstrate that phosphorylation of CRMP2 at Ser522 (Cdk5-mediated) is increased in Alzheimer’s disease (AD) brain, while CRMP2 expression and phosphorylation of the closely related isoform CRMP4 are not altered. In addition, CRMP2 phosphorylation at the Cdk5 and GSK3 sites is increased in cortex and hippocampus of the triple transgenic mouse [presenilin-1 (PS1)M146VKI; Thy1.2-amyloid precursor protein (APP)swe; Thy1.2tauP301L] that develops AD-like plaques and tangles, as well as the double (PS1M146VKI; Thy1.2-APPswe) transgenic mouse. The hyperphosphorylation is similar in magnitude to that in human AD and is evident by 2 months of age, ahead of plaque or tangle formation. Meanwhile, there is no change in CRMP2 phosphorylation in two other transgenic mouse lines that display elevated amyloid β peptide levels (Tg2576 and APP/amyloid β-binding alcohol dehydrogenase). Similarly, CRMP2 phosphorylation is normal in hippocampus and cortex of Tau(P301L) mice that develop tangles but not plaques. These observations implicate hyperphosphorylation of CRMP2 as an early event in the development of AD and suggest that it can be induced by a severe APP over-expression and/or processing defect.
The amyloid-beta-dependent phosphorylation of CRMP-2 dissociates kinesin in Alzheimer’s disease
Alzheimer's & Dementia, 2015
identification of biomarkers predicting the risk of developing AD in asymptomatic subjects could provide key insights into the biology and permit risk stratification and targeted preventive intervention in the early stages of AD, prior to onset of clinical symptoms. We used a metabolomics based approach to identify plasma biomarkers potentially associated with risk of developing dementia. Methods: 2067 dementia-free participants from the Framingham Offspring study (mean age¼55.969.7 years; 52.4% women) had comprehensive blood metabolite assessment on sera stored at their 5 th examination (1991-1995) using liquid chromatography-mass spectrometry (LC-MS) and have also been prospectively assessed for incident dementia (mean follow-up ¼ 15.665.2 years). We used multivariate Cox models to relate log-transformed levels of 217metabolites to dementia occurrence, adjusting for age, sex, APOEε4, education and plasma homocysteine. A metabolite set enrichment analysis (MSEA) was also performed using Metaboanalyst 3.0 including all metabolites with a p-value 0.1. Results: A total of 93 participants developed incident dementia. After correction for multiple testing, only plasma anthranilic acid levels were significantly associated with risk of incident dementia (HR¼1.40; 95% CI¼[1.15-1.70] per standard deviation increase in level; p¼8.08310-4). Three additional biologically plausible metabolites reached nominal significance: glutamic acid (HR¼1.38; 95% CI¼[1.11-1.72]; p¼3.80310-3), taurine (HR¼0.74; 95% CI¼[0.60-0.92]; p¼6.91310-3) and hypoxanthine (HR¼0.74; 95% CI¼[0.60-0.92]; p¼6.93310-3). Using a set a 28 metabolites with a p-value 0.1, we observed a nominally significant enrichment for metabolites related to stroke (p¼2.77310-2). Conclusions: We have identified four candidate plasma biomarkers for dementia, each of which has been previously associated with dementia risk in small cerebrospinal fluid and nuclear magnetic resonance metabolomics studies. The MSEA adds to the evidence for an important vascular contribution to dementia and AD. We are now attempting to replicate these results through collaborations and study of various endophenotypes.
Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer's Disease
Science, 2005
We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-β peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of β-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.
Towards a cure for dementia: the role of axonal transport in Alzheimer’s disease
Alzheimer’s disease is an incurable, fatal illness characterised by years of progressive mental decline. It afflicts half a million people in the UK - more than any other dementia. The primary risk factor is old age so this number is rising as we live longer. Current treatment is palliative while more potent drugs have encountered problems during clinical trials. It is known that the disease results from brain deterioration associated with the formation of microscopic lesions. Genetic mutations cause a small minority of cases but our knowledge of the underlying biological mechanisms is limited. The key to improved understanding may be a process vital to brain cells called axonal transport. Disruption of axonal transport seems to be an early event in the progression of the disease and is linked to lesion formation and brain dysfunction so a full investigation of this process should lead to a cure, if not prevention. Keywords: Alzheimer’s disease, axonal transport, kinesin, microtubule, amyloid hypothesis, tau hypothesis Wilson RJ (2008) Towards a cure for dementia: the role of axonal transport in Alzheimer’s disease. Science Progress 91(1), 65–80 PMID: 18453283
2013
Disruption to axonal transport is an early pathological feature in Alzheimer's disease. The amyloid precursor protein (APP) is a key axonal transport cargo in Alzheimer's disease since perturbation of its transport increases APP processing and production of amyloid-b peptide (Ab) that is deposited in the brains of Alzheimer's disease patients. APP is transported anterogradely through axons on kinesin-1 motors. One favoured route for attachment of APP to kinesin-1 involves the scaffolding protein c-Jun N-terminal kinase-interacting protein-1 (JIP1), which has been shown to bind both APP and kinesin-1 light chain (KLC). However, direct experimental evidence to support a role of JIP1 in APP transport is lacking. Notably, the effect of loss of JIP1 on movement of APP through axons of living neurons, and the impact of such loss on APP processing and Ab production has not been reported. To address these issues, we monitored how siRNA mediated loss of JIP1 influenced transport of enhanced green fluorescent protein (EGFP)-tagged APP through axons and production of endogenous Ab in living neurons. Surprisingly, we found that knockdown of JIP1 did not affect either APP transport or Ab production. These results have important implications for our understanding of APP trafficking in Alzheimer's disease.
Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases
Neurobiology of Disease, 2017
Neurons affected in a wide variety of unrelated adult-onset neurodegenerative diseases (AONDs) typically exhibit a "dying back" pattern of degeneration, which is characterized by early deficits in synaptic function and neuritic pathology long before neuronal cell death. Consistent with this observation, multiple unrelated AONDs including Alzheimer's disease, Parkinson's disease, Huntington's disease, and several motor neuron diseases feature early alterations in kinase-based signaling pathways associated with deficits in axonal transport (AT), a complex cellular process involving multiple intracellular trafficking events powered by microtubule-based motor proteins. These pathogenic events have important therapeutic implications, suggesting that a focus on preservation of neuronal connections may be more effective to treat AONDs than addressing neuronal cell death. While the molecular mechanisms underlying AT abnormalities in AONDs are still being analyzed, evidence has accumulated linking those to a well-established pathological hallmark of multiple AONDs: altered patterns of neuronal protein phosphorylation. Here, we present a short overview on the biochemical heterogeneity of major motor proteins for AT, their regulation by protein kinases, and evidence revealing cell type-specific AT specializations. When considered together, these findings may help explain how independent pathogenic pathways can affect AT differentially in the context of each AOND.