Experimental Diabetes Mellitus Exacerbates Tau Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Ke, Yazi D.; Delerue, Fabien; Gladbach, Amadeus; Götz, Jürgen; Ittner, Lars M.

doi:10.1371/journal.pone.0007917

Cited by 174 publications

(124 citation statements)

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“…Decreased insulin signaling leaves cells vulnerable to oxidative stress and other metabolic insults and can increase inflammation and even tau phosphorylation (Bosco et al, 2011). Experimental diabetes mellitus exacerbates tau pathology in a transgenic mouse model of AD (Ke et al, 2009). The diabetes drug liraglutide has been shown to decrease neuropathology in a transgenic mouse model of AD (McClean et al, 2011), suggesting possible usefulness in AD.…”

Section: Discussionmentioning

confidence: 99%

Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A

Wang¹,

Bakshi²,

Frankfurt³

et al. 2012

Journal of Neuroscience

119

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PTI-125 is a novel compound demonstrating a promising new approach to treating IntroductionAlzheimer's disease (AD) represents one of the greatest health care burdens, affecting 35 million persons worldwide and an estimated 115 million persons by 2050 (Wimo and Prince, 2010). AD is a devastating dementia that first presents as progressive memory loss and later can include neuropsychiatric symptoms. Diagnosis is confirmed at autopsy by amyloid deposits and neurofibrillary tangles (NFTs) containing the microtubuleassociated protein tau. This neuropathology is estimated to precede symptoms by 10 years (Trojanowski et al., 2010). Current AD treatment is limited to acetylcholinesterase inhibitors, with mild and short-lived cognitive enhancement, and memantine, an NMDAR antagonist that may delay some later stage symptoms.Amyloid-␤ (A␤), in particular A␤ 42 , is commonly recognized as the principal causative agent in AD, though its mechanism is debated. Cognitive impairment and the magnitude of synaptic deficit in the AD brain are more highly correlated with soluble A␤ than with the abundance of amyloid plaques, suggesting that soluble A␤ inflicts synaptic impairment (Naslund et al., 2000). Robust evidence demonstrates that soluble A␤ elicits a toxic signaling cascade by the ␣7-nicotinic acetylcholine receptor (␣7nAChR), leading to impaired synaptic activities, intraneuronal A␤ 42 aggregates, and cognitive deficits (Liu et al., 2001;Pettit et al., 2001;Chen et al., 2006;Dziewczapolski et al., 2009;Wang et al., 2009). This aberrant signaling activates the kinases ERK2 and JNK1, which phosphorylate tau, leading to the formation of NFTs .A␤ 42 binds ␣7nAChR with femtomolar affinity (Wang et al., 2000a,b); therefore, to prevent A␤ 42 -induced ␣7nAChR toxic signaling, anti-A␤ therapies must either compete with this extremely high-affinity interaction or essentially eliminate all A␤ 42 . After the initial femtomolar interaction, numerous A␤ 42 molecules bind the receptor, eventually causing internalization and amyloid plaques. These additional A␤ 42 molecules appear to bind at a lower (picomolar) affinity (Wang et al., 2009); hence, it is possible to remove sufficient amounts of A␤ 42 to prevent plaque formation without any impact on the toxic signaling by the highaffinity A␤ 42 -␣7nAChR interaction. Furthermore, pharmacotherapies aiming to prevent A␤ 42 binding to ␣7nAChRs by directly targeting the receptor could, unfortunately, alter ␣7nAChR sensitivity or cell surface expression, especially if they surpass subpicomolar affinity. Alternative strategies to reduce A␤ 42 signaling by ␣7nAChR are needed.We show here that A␤ 42 toxic signaling requires the recruitment of the scaffolding protein filamin A (FLNA), which otherwise has very low levels of association with ␣7nAChR. Filamins are large cytoplasmic proteins best known for crosslinking actin but increasingly implicated in cell signaling (Stossel et al., 2001 A␤-induced FLNA recruitment to ␣7nAChRs and to reduce A␤ 42 signaling. PTI-125 decreases A␤ 42 affinity for ␣7nAC...

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Section: Discussionmentioning

confidence: 99%

Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A

Wang¹,

Bakshi²,

Frankfurt³

et al. 2012

Journal of Neuroscience

119

View full text Add to dashboard Cite

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“…A decrease in insulin availability in the TG mice in this study may explain the increase in GLUT1. It has been found that depletion of insulin, which decreases HIF-1a, can induce hyperglycemic conditions in which blood glucose levels are increased (Ke et al 2009). Furthermore, conditions of hyperglycemia-induced insulin resistance can lead to enhanced glucose transport through insulin-independent GLUT1 and the hexosamine pathway, instead of through GLUT4 (Ebeling et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice

et al. 2012

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Deferoxamine (DFO), a metal chelator, has been previously reported to slow the loss of spatial memory in a mouse model of amyloid accumulation when delivered intranasally (IN). In this study, we determined whether IN DFO also has beneficial effects in the P301L mouse, which accumulates hyperphosphorylated tau. Mice were intranasally treated three times per week with either 10% DFO (2.4 mg) or saline for 5 months, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with Western blot and ELISA. Wild-type (WT) mice statistically outperformed transgenic (TG) saline mice in the radial arm water maze, while performance of TG-DFO mice was not different than WT mice, suggesting improved performance in the radial arm water maze. Other behavioral changes were not evident. Beneficial changes in brain biochemistry were evident in DFO-treated mice for several proteins. The TG mice had significantly less pGSK3β and HIF-1α, with more interleukin-1β and total protein oxidation than wild-type controls, and for each protein, DFO treatment significantly reduced these differences. There was not a significant decrease in phosphorylated tau in brain tissue of DFO-treated mice at the sites we measured. These data suggest that IN DFO is a potential treatment not only for Alzheimer's disease, but also for other neurodegenerative diseases and psychiatric disorders in which GSK3β and HIF-1α play a prominent role.

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“…Proteins were extracted according to solubility as described, using FA or sarkosyl (49,50). Western blotting was performed as described (51).…”

Section: Neuroscience Methodsmentioning

confidence: 99%

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.

Self Cite

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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Experimental Diabetes Mellitus Exacerbates Tau Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Cited by 174 publications

References 39 publications

Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A

Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A

Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice

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

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