Phosphorylation of Actin-Depolymerizing Factor/Cofilin by LIM-Kinase Mediates Amyloid  -Induced Degeneration: A Potential Mechanism of Neuronal Dystrophy in Alzheimer's Disease

Heredia, Lorena; Helguera, Pablo; Olmos, Soledad de; Kedikian, Gabriela; Vigo, Francisco Solá; LaFerla, Frank M.; Staufenbiel, Matthias; Olmos, José de; Busciglio, Jorge; Cáceres, Alfredo; Lorenzo, Alfredo

doi:10.1523/jneurosci.5567-05.2006

Cited by 164 publications

(129 citation statements)

References 67 publications

(97 reference statements)

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“…Similar to the pattern with active PAK, active LIMK1 is found in dystrophic neurites and clusters of neurons in AD, whereas excessive downstream activation of LIMK1, cofilin inactivation, and dystrophic neurites occurred as a rapid response to A␤ fibril treatment (49). Compounds targeting PAK activation in AD might have a narrow therapeutic window because PAKs play important roles in cognition and many other cell functions.…”

Section: Discussionmentioning

confidence: 71%

p21-activated Kinase-aberrant Activation and Translocation in Alzheimer Disease Pathogenesis

Ma¹,

Yang²,

Calon

et al. 2008

Journal of Biological Chemistry

114

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Defects in dendritic spines and synapses contribute to cognitive deficits in mental retardation syndromes and, potentially, Alzheimer disease. p21-activated kinases (PAKs) regulate actin filaments and morphogenesis of dendritic spines regulated by the Rho family GTPases Rac and Cdc42. We previously reported that active PAK was markedly reduced in Alzheimer disease cytosol, accompanied by downstream loss of the spine actinregulatory protein Drebrin. ␤-Amyloid (A␤) oligomer was implicated in PAK defects. Here we demonstrate that PAK is aberrantly activated and translocated from cytosol to membrane in Alzheimer disease brain and in 22-month-old Tg2576 transgenic mice with Alzheimer disease. This active PAK coimmunoprecipitated with the small GTPase Rac and both translocated to granules. A␤ 42 oligomer treatment of cultured hippocampal neurons induced similar effects, accompanied by reduction of dendrites that were protected by kinase-active but not kinase-dead PAK. A␤ 42 oligomer treatment also significantly reduced N-methyl-D-aspartic acid receptor subunit NR2B phosphotyrosine labeling. The Src family tyrosine kinase inhibitor PP2 significantly blocked the PAK/Rac translocation but not the loss of p-NR2B in A␤ 42 oligomer-treated neurons. Src family kinases are known to phosphorylate the Rac activator Tiam1, which has recently been shown to be A␤-responsive. In addition, anti-oligomer curcumin comparatively suppressed PAK translocation in aged Tg2576 transgenic mice with Alzheimer amyloid pathology and in A␤ 42 oligomer-treated cultured hippocampal neurons. Our results implicate aberrant PAK in A␤ oligomer-induced signaling and synaptic deficits in Alzheimer disease. Cognitive deficits in Alzheimer disease (AD)2 correlate with progressive synaptic dysfunction and loss that may be initiated by soluble ␤-amyloid peptide 1-42 (A␤ 42 ) and driven further by the accumulating neuropathological hallmarks, including intraneuronal neurofibrillary tangles, extracellular amyloid plaques, and neuron loss. Soluble A␤ or A␤ oligomers correlate highly with synapse loss (1, 2) and the degree of dementia (3). They also potently inhibit long term potentiation (LTP) in vivo (4). A␤-induced synaptic dysfunction likely contributes to cognitive deficits in several different AD transgenic mouse models (5-7).Both dystrophic neurites and dendritic spine loss are observed in AD and many mental retardation syndromes (8 -10). Dendritic spines, major sites of synaptic contacts, are structurally reliant on the actin cytoskeleton. p21-activated kinases (PAK) (11) are a family of serine/threonine protein kinases involved in regulating the actin-severing protein cofilin, the actin cytoskeleton, and dendritic function as downstream effectors of Rac1/Cdc42 (12). Thus, the small GTPases (Rho, Rac, and Cdc42) play critical roles in regulating dendrite initiation, growth, branching, spinogenesis, and spine maintenance (13-15). Mutations in PAK3 are associated with X-linked nonsyndromic forms of mental retardation, in which the only distinctive clinica...

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Section: Discussionmentioning

confidence: 71%

p21-activated Kinase-aberrant Activation and Translocation in Alzheimer Disease Pathogenesis

Ma¹,

Yang²,

Calon

et al. 2008

Journal of Biological Chemistry

114

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“…Intriguingly a recent study reported a significant increase in phosphorylated LIMK1 in neurons of brain areas affected with AD pathology. This finding suggests that LIMK signaling may also play a role in the pathology of AD, acting downstream of PAK [37] …”

Section: Pak3mentioning

confidence: 86%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3 % of children and young adults. MR has been consistently associated with changes in dendrites and dendritic spine structure. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to be the underlying cause of cognitive disabilities observed in MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore naturally attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. In support of this, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotropic lateral sclerosis (ALS). Here we will discuss Rho GTPase related genes and their signaling pathways involved in MR and ALS.

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“…[97][98][99] Note that active LIM kinase (LIMK) is also a downstream effector of A␤-mediated toxicity. 100 Pharmacological inhibitors of MARK/MARKK include staurosporine (unselectively) and hymenialdisine, which also inhibits GSK3␤. 90,101 Given the important and early role of MARK phosphorylation in the pathogenesis of tauopathies, the application of MARK inhibitors would be a worthwhile approach.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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Phosphorylation of Actin-Depolymerizing Factor/Cofilin by LIM-Kinase Mediates Amyloid -Induced Degeneration: A Potential Mechanism of Neuronal Dystrophy in Alzheimer's Disease

Cited by 164 publications

References 67 publications

p21-activated Kinase-aberrant Activation and Translocation in Alzheimer Disease Pathogenesis

p21-activated Kinase-aberrant Activation and Translocation in Alzheimer Disease Pathogenesis

Rho-linked genes and neurological disorders

Tau-Based Treatment Strategies in Neurodegenerative Diseases

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