Differential Expression of Synaptic Proteins in the Frontal and Temporal Cortex of Elderly Subjects With Mild Cognitive Impairment

Counts, Scott; Nadeem, Muhammad; Lad, Shivanand P.; Wuu, Joanne; Mufson, Elliott J.

doi:10.1097/00005072-200606000-00007

Cited by 188 publications

(191 citation statements)

References 54 publications

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“…4, B, C, and E). A␤ oligomer-induced spine loss is consistent with alterations found in AD brain and in transgenic mouse AD models (19,26,27) and in vitro models with oligomer treatments (28), further supporting the hypothesis that oligomer-induced deficits may play a significant role in synaptic dysfunction and synapse loss in AD.…”

Section: Pak Translocation In Appsw Tg2576supporting

confidence: 75%

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

Ma¹,

Yang²,

Calon

et al. 2008

Journal of Biological Chemistry

112

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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: Pak Translocation In Appsw Tg2576supporting

confidence: 75%

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

Ma¹,

Yang²,

Calon

et al. 2008

Journal of Biological Chemistry

112

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“…Current results confirm that ADDLs cause a major loss of surface NMDARs. Loss of these receptors has been shown in AD brain (Sze et al, 2001;Mishizen-Eberz et al, 2004) and Tg2576 mice (Snyder et al, 2005) and correlates with synaptic alterations and cognitive deficits (Terry et al, 1991;Sze et al, 1997;Counts et al, 2006). The large decrease in receptor expression seen here occurs before any major change in spine density, consistent with synaptic plasticity being compromised before degeneration.…”

Section: Discussionsupporting

confidence: 62%

“…The average number of puncta per length of dendrite for ADDL treated was normalized against the mean value of vehicle treated. 2004; Spires et al, 2005;Counts et al, 2006;Jacobsen et al, 2006), which is considered the best correlate of dementia (DeKosky and Scheff, 1990;Terry et al, 1991;Sze et al, 1997). Tg mice also exhibit decreased drebrin (Calon et al, 2004), consistent with loss of spines.…”

Section: Decreased Spine Density and Loss Of Drebrin Caused By Addl Ementioning

confidence: 97%

“…Recent evidence suggests that synapse degeneration begins at the level of dendritic spines, which are the loci of memory-initiating mechanisms (Harris and Kater, 1994;Morris and Davis, 1994;Carlisle and Kennedy, 2005;Segal, 2005). In AD and transgenic (Tg) mouse AD models, significant decreases occur in spine density (Ferrer and Gullotta, 1990;Moolman et al, 2004;Spires et al, 2005;Jacobsen et al, 2006) and in molecules involved in spine signaling (Sze et al, 2001;Mishizen-Eberz et al, 2004) and control of filamentous actin (F-actin) (Harigaya et al, 1996;Shim and Lubec, 2002;Counts et al, 2006). Conceivably, AD dementia may be initiated before synapse degeneration by spine aberrations.…”

Section: Introductionmentioning

confidence: 99%

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Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease

Lacor

Buniel²,

Furlow³

et al. 2007

J. Neurosci.

1,059

923

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The basis for memory loss in early Alzheimer's disease (AD) seems likely to involve synaptic damage caused by soluble A␤-derived oligomers (ADDLs). ADDLs have been shown to build up in the brain and CSF of AD patients and are known to interfere with mechanisms of synaptic plasticity, acting as gain-of-function ligands that attach to synapses. Because of the correlation between AD dementia and synaptic degeneration, we investigated here the ability of ADDLs to affect synapse composition, structure, and abundance. Using highly differentiated cultures of hippocampal neurons, a preferred model for studies of synapse cell biology, we found that ADDLs bound to neurons with specificity, attaching to presumed excitatory pyramidal neurons but not GABAergic neurons. Fractionation of ADDLs bound to forebrain synaptosomes showed association with postsynaptic density complexes containing NMDA receptors, consistent with observed attachment of ADDLs to dendritic spines. During binding to hippocampal neurons, ADDLs promoted a rapid decrease in membrane expression of memory-related receptors (NMDA and EphB2). Continued exposure resulted in abnormal spine morphology, with induction of long thin spines reminiscent of the morphology found in mental retardation, deafferentation, and prionoses. Ultimately, ADDLs caused a significant decrease in spine density. Synaptic deterioration, which was accompanied by decreased levels of the spine cytoskeletal protein drebrin, was blocked by the Alzheimer's therapeutic drug Namenda. The observed disruption of dendritic spines links ADDLs to a major facet of AD pathology, providing strong evidence that ADDLs in AD brain cause neuropil damage believed to underlie dementia.

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“…Frozen cortex tissue samples were prepared as previously described 51 . Samples were randomized based on diagnostic group and assayed in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

Self Cite

474

368

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Alzheimer’s disease (AD) is a common and devastating disease characterized by the aggregation of amyloid-β peptide (Aβ), yet we know relatively little about the underlying molecular mechanisms or how to treat AD patients. Here, we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in Aβ proteotoxic diseases in human, mouse and C. elegans, and which involves the UPRmt and mitophagy pathways. Using the worm model of Aβ proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed the induction of this mitochondrial stress response as key to maintain mitochondrial proteostasis and health. Importantly, boosting mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms, and in AD transgenic mice. Our data support the relevance of enhancing mitochondrial proteostasis to delay Aβ proteotoxic diseases, such as AD.

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Differential Expression of Synaptic Proteins in the Frontal and Temporal Cortex of Elderly Subjects With Mild Cognitive Impairment

Cited by 188 publications

References 54 publications

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

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

Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

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