Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease

Chin, Jeannie; Palop, Jorge J.; Puoliväli, Jukka; Massaro, Catherine; Bien-Ly, Nga; Gerstein, Hilary; Scearce‐Levie, Kimberly; Masliah, Eliezer; Mucke, Lennart

doi:10.1523/jneurosci.2980-05.2005

Cited by 294 publications

(284 citation statements)

References 68 publications

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“…To increase the survival of mice coexpressing hAPP/Aβ and hTau‐A152T, we crossed hTau‐A152T (L1) mice with mice from hAPP line J9 (hAPP‐J9), which express hAPP/Aβ at lower levels than hAPP‐J20 mice 50, 54, 55, 56. Among 282 offspring from crosses of hTau‐A152T (L1) and hAPP‐J9 mice, only eight were triply transgenic (Fig 11E).…”

Section: Resultsmentioning

confidence: 99%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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A152T‐variant human tau (hTau‐A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau‐A152T or wild‐type hTau (hTau‐WT), we find age‐dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau‐A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau‐A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau‐A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co‐expression of hTau‐A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau‐A152T and amyloid‐β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors.

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Section: Resultsmentioning

confidence: 99%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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“…ARC48 mice showed a trend toward hyperactivity. J20 mice (38,39) and other hAPP models (37) also show an abnormal phenotype in the elevated plus maze, which is widely used to assess emotionality (40). In this test, ARC6 mice again behaved normally, whereas J20 mice and ARC48 mice traveled longer distances on the open arms of the maze than NTG controls (Fig.…”

Section: The Arctic Mutation Markedly Increases the Ratio Of Fibrillarmentioning

confidence: 81%

“…Water-maze deficits in J20 mice also correlate well with the depletion of calcium-and synaptic activity-related proteins in granule cells of the dentate gyrus (20,38,44). The calciumbinding protein calbindin-D28K and the immediate-early gene product Fos are among the most robust and sensitive of these biomarkers.…”

Section: The Arctic Mutation Markedly Increases the Ratio Of Fibrillarmentioning

confidence: 99%

Accelerating Amyloid-β Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models

Cheng

Scearce‐Levie

Legleiter

et al. 2007

Journal of Biological Chemistry

390

364

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Many proteins suspected of causing neurodegenerative diseases exist in diverse assembly states. For most, it is unclear whether shifts from one state to another would be helpful or harmful. We used mutagenesis to change the assembly state of Alzheimer disease (AD)-associated amyloid-␤ (A␤) peptides. In vitro, the "Arctic" mutation (A␤E22G) accelerated A␤ fibrillization but decreased the abundance of nonfibrillar A␤ assemblies, compared with wild-type A␤. In human amyloid precursor protein (hAPP) transgenic mice carrying mutations adjacent to A␤ that increase A␤ production, addition of the Arctic mutation markedly enhanced the formation of neuritic amyloid plaques but reduced the relative abundance of a specific nonfibrillar A␤ assembly (A␤*56). Mice overexpressing Arctic mutant or wildtype A␤ had similar behavioral and neuronal deficits when they were matched for A␤*56 levels but had vastly different plaque loads. Thus, A␤*56 is a likelier determinant of functional deficits in hAPP mice than fibrillar A␤ deposits. Therapeutic interventions that reduce A␤ fibrils at the cost of augmenting nonfibrillar A␤ assemblies could be harmful. Alzheimer disease (AD)3 and many other neurodegenerative disorders are associated with the accumulation of abnormal protein assemblies in the central nervous system (CNS). Much evidence suggests that this association reflects a causal relationship in which the abnormal proteins actually trigger the neuronal dysfunction and degeneration that characterize these conditions (1-3). The prevalence of AD and other neurodegenerative proteinopathies is increasing rapidly around the world, most likely because of their age dependence, the increasing longevity of many populations, and the lack of effective strategies for treatment and prevention (4 -6). This alarming trend underlines the need to better understand the relationship between the accumulation of abnormal proteins in the CNS and the decline of neurological function.This relationship has been difficult to analyze in depth because proteins associated with neurodegenerative disorders can exist in diverse assembly states, and distinct assemblies can differ markedly in pathogenic potential. For example, the amyloid-␤ (A␤) peptide, which seems to play a causal role in AD, can exist as monomers, low molecular weight oligomers (such as dimers and trimers), larger globular oligomers (such as A␤*56, A␤-derived diffusible ligands, amylospheroids, and globulomers), amyloid pores, protofibrils, fibrils, and amyloid plaques that contain densely packed A␤ fibrils and a large number of other molecules and cellular elements (7-15). Which of these structures contributes most critically to neurological decline in AD is a matter of active study and debate that has important implications for therapeutic interventions. Studies of transgenic mice with neuronal expression of human amyloid precursor proteins (hAPP), from which A␤ is released by proteolytic cleavage, suggest that nonfibrillar A␤ assemblies are more critical than amyloid plaques in the pathogene...

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“…PAK could also be activated through direct interaction with candidate A␤ receptors (X), for example, the amyloid precursor protein (47) or indirectly via Src/Fyn activation of Tiam1. Although the A␤ receptors are not clearly established, A␤-mediated in vivo synaptotoxicity and in vitro LTP deficits are both Fyn kinase- (32,33) and NMDA receptor-dependent (1, 2). The Src family kinase Fyn is also physically associated with at least two candidate A␤ receptors (X), notably integrin receptors (51,52) and ␣ 7 -nicotinic receptors (53), suggesting they could activate Fyn to mediate deranged downstream Rac/PAK translocation and signaling caused by A␤ oligomers, which we find blocked by the anti-oligomer drug curcumin.…”

Section: Discussionmentioning

confidence: 99%

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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Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease

Cited by 294 publications

References 68 publications

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Accelerating Amyloid-β Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models

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

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