Drebrin, a dendritic spine protein, is manifold decreased in brains of patients with Alzheimer's disease and Down syndrome

Shim, Ki Shuk; Lubec, Gert

doi:10.1016/s0304-3940(02)00210-0

Cited by 170 publications

(120 citation statements)

References 18 publications

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“…We also find that Bcl11b expression deficits worsen with disease progression in mice and are dramatically reduced in the brains of human subjects with end-stage illness. It is possible some of the observed decrease in Bcl11b expression in human caudate could be due to neuronal loss, however this is not likely to explain the total decrease, as no changes in the mRNA or protein levels of beta-actin, which is commonly used to normalize neuronal levels of expression (Shim and Lubec 2002;Smart et al, 2003;Rinaldi et al, 2007), were observed.…”

Section: Discussionmentioning

confidence: 99%

Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

Desplats

Lambert

Thomas

2008

Neurobiology of Disease

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Transcriptional dysregulation has emerged as a central pathogenic mechanism in Huntington's disease (HD), which is associated with neuropathological changes predominantly in the striatum. Here we demonstrate that expression of Bcl11b (a.k.a. CTIP2), a transcription factor exhibiting highly-enriched localization in adult striatum, is significantly decreased in HD cells, mouse models and human subjects and that overexpression of Bcl11b attenuates toxic effects of mutant huntingtin in cultured striatal neurons. We show that Bcl11b directly activates the proximal promoter regions of striatal-enriched genes and can increase mRNA levels of striatal-expressing genes. We further demonstrate an interaction between Bcl11b and huntingtin protein in cultured cells and brain homogenates from HD R6/1 and YAC72 transgenic mice. We propose that sequestration and/or decreased expression of Bcl11b in HD is responsible, at least in part, for the dysregulation of striatal gene expression observed in HD and may contribute to the specificity of pathology observed in this disease.

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Section: Discussionmentioning

confidence: 99%

Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

Desplats

Lambert

Thomas

2008

Neurobiology of Disease

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“…Aged Tg2576 APPsw transgene-positive mice placed from 17 to 22 months on a safflower oil rich, DHA-depleting diet exhibited increased oxidative damage and transgenedependent loss of CNS DHA and massive (70-95%) loss of postsynaptic proteins like the actin-regulatory drebrin, a dendritic spine protein known to be 70-90% lost in AD [7,27] and NR2b [6]. Greater depletion of DHA in Tg2576 may be driven by A␤ aggregates causing DHA oxidation.…”

Section: Omega-3 Fatty Acidsmentioning

confidence: 99%

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

Cole

Lim

Yang

et al. 2005

Neurobiology of Aging

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Alzheimer's disease (AD) and cardiovascular disease (CVD) are syndromes of aging that share analogous lesions and risk factors, involving lipoproteins, oxidative damage and inflammation. Unlike in CVD, in AD, sensitive biomarkers are unknown, and high-risk groups are understudied. To identify potential prevention strategies in AD, we have focused on pre-clinical models (transgenic and amyloid infusion models), testing dietary/lifestyle factors strongly implicated in reducing risk in epidemiological studies. Initially, we reported the impact of non-steroidal anti-inflammatory drugs (NSAIDs), notably ibuprofen, which reduced amyloid accumulation, but suppressed few inflammatory markers and without reducing oxidative damage. Safety concerns with chronic NSAIDs led to a screen of alternative NSAIDs and identification of the phenolic anti-inflammatory/anti-oxidant compound curcumin, the yellow pigment in turmeric that we found targeted multiple AD pathogenic cascades. The dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model. Both DHA and curcumin have favorable safety profiles, epidemiology and efficacy, and may exert general anti-aging benefits (anti-cancer and cardioprotective.)

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“…Drebrin A expression level also seems to be linked to the stability of spines within mature brains. Disappearance of drebrin A occurs prior to the spine loss from various brain regions of Alzheimer's disease and Down syndrome patients (Harigaya et al, 1996;Hatanpaa et al, 1999;Shim and Lubec, 2002). The studies using animal model of Alzheimer's disease also indicate that drebrin level declines as the disease advances toward terminal symptoms (Calon et al, 2004;Zhao et al, 2006).…”

mentioning

confidence: 97%

Drebrin a content correlates with spine head size in the adult mouse cerebral cortex

Kobayashi

Aoki²,

Kojima

et al. 2007

J of Comparative Neurology

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Synaptic activities alter synaptic strengths at the axospinous junctions, and such changes are often accompanied by changes in the size of the postsynaptic spines. We have been exploring the idea that drebrin A, a neuron-specific actin-binding protein localized on the postsynaptic side of excitatory synapses, may be a molecule that links synaptic activity to the shape and content of spines. Here, we performed electron microscopic immunocytochemistry with the nondiffusible gold label to explore the relationship among levels of drebrin A, the NR2A subunit of N-methyl-D-aspartate receptors, and the size of spines in the perirhinal cortex of adult mouse brains. In contrast to the membranous localization within neonatal spines, most immunogold particles for drebrin A were localized to the cytoplasmic core region of spines in mature spines. This distribution suggests that drebrin within adult spines may reorganize the F-actin network at the spine core, in addition to its known neonatal role in spine formation. Drebrin A-immunopositive (DIP) spines exhibited larger spine head areas and longer postsynaptic densities (PSDs) than drebrin A-immunonegative (DIN) spines (P < 0.001). Furthermore, spine head area and PSD lengths correlated positively with drebrin A levels (r = 0.47 and 0.40). The number of synaptic NR2A immunolabels was also higher in DIP spines than in DIN spines, whereas their densities per unit lengths of PSD were not significantly different. These differences between the DIP and the DIN spines indicate that spine sizes and synaptic protein composition of mature brains are regulated, at least in part, by drebrin A levels.

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Drebrin, a dendritic spine protein, is manifold decreased in brains of patients with Alzheimer's disease and Down syndrome

Cited by 170 publications

References 18 publications

Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

Drebrin a content correlates with spine head size in the adult mouse cerebral cortex

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