Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden

Malm, Tarja; Iivonen, Henna; Goldsteins, Gundars; Keksa-Goldsteine, Velta; Ahtoniemi, Toni; Kanninen, Katja M.; Salminen, Antero; Auriola, Seppo; Groen, Thomas van; Tanila, Heikki; Koistinaho, Jari

doi:10.1523/jneurosci.0059-07.2007

Cited by 146 publications

(122 citation statements)

References 82 publications

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“…Administration of minocycline, an anti-inflammatory drug, did not change the levels of total, soluble, or insoluble Ab, while ameliorating behavioral deficits in transgenic mice (Fan et al 2007). Similarly, treatment with dithiocarbamates, which can inhibit the preinflammatory agent NFkB, also improved AD pathology without affecting Ab burden (Malm et al 2007). In addition to anti-inflammatory treatments, the cholesterol-lowering drug simvastatin induced cognitive improvement without changing levels of Ab in transgenic mice (Li et al 2006).…”

Section: Discussionmentioning

confidence: 97%

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

Cao

Song²,

Gangi

et al. 2008

Genetics

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Sustained increases in life expectancy have underscored the importance of managing diseases with a high incidence in late life, such as various neurodegenerative conditions. Alzheimer's disease (AD) is the most common among these, and consequently significant research effort is spent on studying it. Although a lot is known about the pathology of AD and the role of b-amyloid (Ab) peptides, the complete network of interactions regulating Ab metabolism and toxicity still eludes us. To address this, we have conducted genetic interaction screens using transgenic Drosophila expressing Ab and we have identified mutations that affect Ab metabolism and toxicity. These analyses highlight the involvement of various biochemical processes such as secretion, cholesterol homeostasis, and regulation of chromatin structure and function, among others, in mediating toxic Ab effects. Several of the mutations that we identified have not been linked to Ab toxicity before and thus constitute novel potential targets for AD intervention. We additionally tested these mutations for interactions with tau and expanded-polyglutamine overexpression and found a few candidate mutations that may mediate common mechanisms of neurodegeneration. Our data offer insight into the toxicity of Ab and open new areas for further study into AD pathogenesis

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Section: Discussionmentioning

confidence: 97%

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

Cao

Song²,

Gangi

et al. 2008

Genetics

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“…Here, in Tg2576 mice treated with 4-PBA, we found that memory deficits were markedly ameliorated without any alteration in cortical Ab levels and senile plaques, suggesting that 4-PBA does not interfere with Ab production to produce its beneficial effects on learning and memory. Earlier studies have shown that improved learning and memory performance is not always associated with any detectable alteration in brain Ab burden (Dodart et al, 2002;Gong et al, 2004;Malm et al, 2007, Green et al, 2008, suggesting that the relationship between soluble and insoluble brain Ab concentrations and memory impairment in transgenic mice is task specific and complex. In addition, in extensive studies, no clear correlation between deposited forms of Ab (such as plaques) and memory impairment in AD patients has been shown (Hyman et al, 1984;Braak and Braak, 1991).…”

Section: Discussionmentioning

confidence: 99%

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

Ricobaraza

Cuadrado‐Tejedor

Pérez-Mediavilla

et al. 2009

Neuropsychopharmacol

364

265

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Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering b-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3b (GSK3b). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

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“…Furthermore, PBT2 and clioquinol both provided promising cognition outcomes in clinical trials (11,16). In a related study, AD mice were treated for 7 months with the metal-ligating compound pyrrolidine dithiocarbamate (PDTC), and the treatment was shown to induce phosphorylation of Akt and GSK3␤, decrease tau phosphorylation, and improve cognitive performance of the mice (35). Surprisingly, however, PDTC did not change A␤ levels as determined by ELISA.…”

Section: Discussionmentioning

confidence: 99%

Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Crouch

Hung²,

Adlard³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

248

268

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Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-␤ (A␤) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3␤ (GSK3␤) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3␤. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3␤ through activation of an Akt signaling pathway. Our lead compound Cu II (gtsm) significantly inhibited GSK3␤ in the brains of APP/PS1 transgenic AD model mice. Cu II (gtsm) also decreased the abundance of A␤ trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvement in the Y-maze correlated directly with decreased A␤ trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic A␤ trimers and phosphorylated tau.Alzheimer's disease ͉ bioinorganic chemistry ͉ glycogen synthase kinase ͉ therapeutic ͉ animal model A lzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by impaired cognitive performance and pathologically by cerebral deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. Amyloid plaques in AD contain aggregated forms of the 39-to 43-aa amyloid-␤ peptide (A␤) and A␤ is strongly implicated as a causative agent responsible for cognitive failure in AD. A diverse range of mechanisms for A␤ toxicity has been reported (1). A␤ is produced from the amyloid precursor protein (APP) (2-5) and readily aggregates to form insoluble, high-molecular-mass amyloid structures. Intermediates on the A␤ aggregation pathway, primarily low-molecular-mass oligomers such as dimers and trimers, exhibit the greatest neurotoxicity (6-8). In addition to A␤ oligomers, aberrantly phosphor ylated microtubuleassociated protein tau is also associated with cognitive decline in AD (9). Intracellular neurofibrillary tangles in the AD brain contain hyperphosphorylated tau, and A␤ induced cognitive deficits characteristic of AD transgenic mice are attenuated by decreasing levels of endogenous tau (10).It is now widely recognized that a truly effective therapeutic compound for treating AD needs to attenuate both the A␤-and tau-mediated pathologies. Recent positive outcomes for PBT2 in clinical and preclinical trials are therefore pertinent. Lannfelt et al.(11) demonstrated in phase IIa clinical trials that PBT2 lowers plasma A␤ levels and attenuates cognitive decline, and Adlard et al. (12) have shown that PBT2 decreases interstitial A␤ and phosphorylated tau in the brains of AD model mice. PBT2 is a secondgeneration 8-OH quinoline, which, unlike its predecessor clioquinol, lacks iodine and was selected for clinical development because of its easier chemical synthesis, higher solubility, and increased blood-brain barrier perme...

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Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden

Cited by 146 publications

References 82 publications

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

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