Dataset Information

Insulin-Mediated Changes in Tau Hyperphosphorylation and Autophagy in a Drosophila Model of Tauopathy and Neuroblastoma Cells.

ABSTRACT: Almost 50 million people in the world are affected by dementia; the most prevalent form of which is Alzheimer's disease (AD). Although aging is considered to be the main risk factor for AD, growing evidence from epidemiological studies suggests that type 2 diabetes mellitus (T2DM) increases the risk of dementia including AD. Defective brain insulin signaling has been suggested as an early event in AD and other tauopathies but the mechanisms that link these diseases are largely unknown. Tau hyperphosphorylation is a hallmark of neurofibrillary pathology and insulin resistance increases the number of neuritic plaques particularly in AD. Utilizing a combination of our Drosophila models of tauopathy (expressing the 2N4R-Tau) and neuroblastoma cells, we have attempted to decipher the pathways downstream of the insulin signaling cascade that lead to tau hyperphosphorylation, aggregation and autophagic defects. Using cell-based, genetic, and biochemical approaches we have demonstrated that tau phosphorylation at AT8 and PHF1 residues is enhanced in an insulin-resistant environment. We also show that insulin-induced changes in total and phospho-tau are mediated by the crosstalk of AKT, glycogen synthase kinase-3?, and extracellular regulating kinase located downstream of the insulin receptor pathway. Finally, we demonstrate a significant change in the levels of the key proteins in the mammalian target of rapamycin/autophagy pathway, implying an increased impairment of aggregated protein clearance in our transgenic Drosophila models and cultured neuroblastoma cells.

SUBMITTER: Chatterjee S

PROVIDER: S-EPMC6688711 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Insulin-Mediated Changes in Tau Hyperphosphorylation and Autophagy in a <i>Drosophila</i> Model of Tauopathy and Neuroblastoma Cells.

Chatterjee Shreyasi S Ambegaokar Suren S SS Jackson George R GR Mudher Amritpal A

Frontiers in neuroscience 20190802

Almost 50 million people in the world are affected by dementia; the most prevalent form of which is Alzheimer's disease (AD). Although aging is considered to be the main risk factor for AD, growing evidence from epidemiological studies suggests that type 2 diabetes mellitus (T2DM) increases the risk of dementia including AD. Defective brain insulin signaling has been suggested as an early event in AD and other tauopathies but the mechanisms that link these diseases are largely unknown. Tau hyper ...[more]

PMID: 31427921

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Project description:Inflammation is considered a mechanistic driver of Alzheimer's disease, thought to increase tau phosphorylation, the first step to the formation of neurofibrillary tangles (NFTs). To further understand how inflammation impacts the development of tau pathology, we used (hTau) mice, which express all six, non-mutated, human tau isoforms, but with an altered ratio of tau isoforms favoring 3R tau due to the concomitant loss of murine tau (mTau) that is predominantly 4R. Such an imbalance pattern has been related to susceptibility to NFTs formation, but whether or not this also affects susceptibility to systemic inflammation and related changes in tau phosphorylation is not known. To reduce the predominance of 3R tau by increasing 4R tau availability, we bred hTau mice on a heterozygous mTau background and compared the impact of systemic inflammation induced by lipopolysaccharide (LPS) in hTau mice hetero- or homozygous mTau knockout. Three-month-old male wild-type (Wt), mTau+/-, mTau-/-, hTau/mTau+/-, and hTau/mTau-/- mice were administered 100, 250, or 330 μg/kg of LPS or its vehicle phosphate buffer saline (PBS) [intravenously (i.v.), n = 8-9/group]. Sickness behavior, reflected by behavioral suppression in the spontaneous alternation task, hippocampal tau phosphorylation, measured by western immunoblotting, and circulating cytokine levels were quantified 4 h after LPS administration. The persistence of the LPS effects (250 μg/kg) on these measures, and food burrowing behavior, was assessed at 24 h post-inoculation in Wt, mTau+/-, and hTau/mTau+/- mice (n = 9-10/group). In the absence of immune stimulation, increasing 4R tau levels in hTau/mTau+/- exacerbated pS202 and pS396/404 tau phosphorylation, without altering total tau levels or worsening early behavioral perturbations characteristic of hTau/mTau-/- mice. We also show for the first time that modulating 4R tau levels in hTau mice affects the response to systemic inflammation. Behavior was suppressed in all genotypes 4 h following LPS administration, but hTau/mTau+/- exhibited more severe sickness behavior at the 100 μg/kg dose and a milder behavioral and cytokine response than hTau/mTau-/- mice at the 330 μg/kg dose. All LPS doses decreased tau phosphorylation at both epitopes in hTau/mTau+/- mice, but pS202 levels were selectively reduced at the 100 μg/kg dose in hTau/mTau-/- mice. Behavioral suppression and decreased tau phosphorylation persisted at 24 h following LPS administration in hTau/mTau+/- mice.

Project description:BackgroundTauopathies comprise a family of neurodegenerative disorders including Alzheimer's disease for which there is an urgent and unmet need for disease-modifying treatments. Tauopathies are characterized by pathological tau hyperphosphorylation, which has been shown to correlate tightly with disease progression and memory loss in patients suffering from Alzheimer's disease. We recently demonstrated an essential requirement for 3-O-sulfated heparan sulfate in pathological tau hyperphosphorylation in zebrafish, a prominent model organism for human drug discovery. Here, we investigated whether in vivo treatment with surfen or its derivatives oxalyl surfen and hemisurfen, small molecules with heparan sulfate antagonist properties, could mitigate tau hyperphosphorylation and neuronal deficits in a zebrafish model of tauopathies.ResultsIn vivo treatment of Tg[HuC::hTauP301L; DsRed] embryos for 2 days with surfen or oxalyl surfen significantly reduced the accumulation of the pThr181 tau phospho-epitope measured by ELISA by 30% and 51%, respectively. Western blot analysis also showed a significant decrease of pThr181 and pSer396/pSer404 in embryos treated with surfen or oxalyl surfen. Immunohistochemical analysis further confirmed that treatment with surfen or oxalyl surfen significantly decreased the AT8 tau epitope in spinal motoneurons. In addition, in vivo treatment of Tg[HuC::hTauP301L; DsRed] embryos with surfen or oxalyl surfen significantly rescued spinal motoneuron axon-branching defects and, as a likely consequence, the impaired stereotypical touch-evoked escape response. Importantly, treatment with hemisurfen, a surfen derivative devoid of heparan sulfate antagonist activity, does not affect tau hyperphosphorylation, nor neuronal or behavioural deficits in Tg[HuC::hTauP301L; DsRed] embryos.ConclusionOur findings demonstrate for the first time that surfen, a well-tolerated molecule in clinical settings, and its derivative, oxalyl surfen, could mitigate or delay neuronal defects in tauopathies, including Alzheimer's disease.

Project description:APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

Dataset Information

Insulin-Mediated Changes in Tau Hyperphosphorylation and Autophagy in a Drosophila Model of Tauopathy and Neuroblastoma Cells.

Publications

Insulin-Mediated Changes in Tau Hyperphosphorylation and Autophagy in a <i>Drosophila</i> Model of Tauopathy and Neuroblastoma Cells.

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