PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer's Disease Hippocampus

Vogelsberg-Ragaglia, Vanessa; Schuck, Theresa; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1006/exnr.2001.7630

Cited by 262 publications

(182 citation statements)

References 55 publications

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“…These results are consistent with reports demonstrating that in vivo inhibition of phosphatases by okadaic acid (Arendt et al, 1998), or by expression of a dominantnegative mutant form of the catalytic subunit of PP2A (Kins et al, 2001), lead to abnormal tau hyperphosphorylation. PP2A is likely the major tau phosphatase in vivo, and its expression level and activity are decreased in AD brains (Gong et al, 1993(Gong et al, , 1995Vogelsberg-Ragaglia et al, 2001). Together, our results provide additional in vivo evidence for a crucial role of PP2A defects in abnormal tau hyperphosphorylation in AD.…”

Section: Discussionsupporting

confidence: 53%

Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

Planel¹,

Miyasaka²,

et al. 2004

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Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein.Regional reductions in cerebral glucose metabolism correlating to NFT densities have been reported in AD brains. Assuming that reduced glucose metabolism might cause abnormal tau hyperphosphorylation, we induced in vivo alterations of glucose metabolism in mice by starvation or intraperitoneal injections of either insulin or deoxyglucose. We found that the treatments led to abnormal tau hyperphosphorylation with patterns resembling those in early AD brains and also resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced down to a differential effect of low temperatures on kinase and phosphatase activities. These data indicate that abnormal tau hyperphosphorylation is associated with altered glucose metabolism through hypothermia. Our results imply that serine-threonine protein phosphatase 2A plays a major role in regulating tau phosphorylation in the adult brain and provide in vivo evidence for its crucial role in abnormal tau hyperphosphorylation in AD.

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Section: Discussionsupporting

confidence: 53%

Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

Planel¹,

Miyasaka²,

et al. 2004

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“…Reduced PP2A activity has been implicated in AD (21,22). Because selenate antagonized the PP2A inhibitor OA in SH-SY5Y cells (Fig.…”

Section: Resultsmentioning

confidence: 96%

Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models

Eersel

Liu

et al. 2010

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

252

204

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Alzheimer's disease (AD) brains are characterized by amyloid-β-containing plaques and hyperphosphorylated tau-containing neurofibrillary tangles (NFTs); however, in frontotemporal dementia, the tau pathology manifests in the absence of overt amyloid-β plaques. Therapeutic strategies so far have primarily been targeting amyloid-β, although those targeting tau are only slowly beginning to emerge. Here, we identify sodium selenate as a compound that reduces tau phosphorylation both in vitro and in vivo. Importantly, chronic oral treatment of two independent tau transgenic mouse strains with NFT pathology, P301L mutant pR5 and K369I mutant K3 mice, reduces tau hyperphosphorylation and completely abrogates NFT formation. Furthermore, treatment improves contextual memory and motor performance, and prevents neurodegeneration. As hyperphosphorylation of tau precedes NFT formation, the effect of selenate on tau phosphorylation was assessed in more detail, a process regulated by both kinases and phosphatases. A major phosphatase implicated in tau dephosphorylation is the serine/threonine-specific protein phosphatase 2A (PP2A) that is reduced in both levels and activity in the AD brain. We found that selenate stabilizes PP2A-tau complexes. Moreover, there was an absence of therapeutic effects in sodium selenate-treated tau transgenic mice that coexpress a dominant-negative mutant form of PP2A, suggesting a mediating role for PP2A. Taken together, sodium selenate mitigates tau pathology in several AD models, making it a promising lead compound for tau-targeted treatments of AD and related dementias.

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“…An association between Aβ and hyperphosphorylated tau has been shown (Ribe et al, 2005;Oddo et al, 2003). Soluble Aβ can induce inactivation of phosphatases (Vogelsberg-Ragaglia et al, 2001) and activation of tau kinases (Hoshi et al, 2003;Otth et al, 2002), and promoting tau phosphorylation (Hoshi et al, 2003;Otth et al, 2002;Zheng et al, 2002) and the direct interaction between tau and Aβ induces tau aggregation and hyperphosphorylation (Rank et al, 2002). In addition, tau seems to be required for the neurotoxic effects of Aβ oligomers (Shipton et al, 2011).…”

Section: Interplay Between Dyrk1a Aβ and Taumentioning

confidence: 99%

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

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PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer's Disease Hippocampus

Cited by 262 publications

References 55 publications

Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

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