The Link Between Tau and Insulin Signaling: Implications for Alzheimer’s Disease and Other Tauopathies

Gonçalves, Rafaella Araújo; Wijesekara, Nadeeja; Fraser, Paul E.; Felice, Fernanda G. De

doi:10.3389/fncel.2019.00017

Cited by 66 publications

(47 citation statements)

References 84 publications

(93 reference statements)

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“…Tau hyperphosphorylation in Alzheimer Disease is generally felt to occur in the middle or late stages of the pathologic cascade leading to Alzheimer Disease (Hampel et al, 2015;Karran et al, 2011), and thus may be a consequence of other toxic or metabolic insults, such as the accumulation of amyloid beta or other molecules. Consistent with this idea is the finding that tau hyperphosphorylation is seen across a number of neurologic diseases (Arendt et al, 2016;Kovacs, 2018), and can be seen in the setting of high stress and glucocorticoid levels (Dey et al, 2017;Rissman et al, 2007), hypothermia (Bretteville et al, 2012;Planel et al, 2007) or diabetes models (Gonçalves et al, 2019;Morales-Corraliza et al, 2016), suggesting that it reflects a response to metabolic stress. In support of the notion that phosphorylation of tau is a consequence of more acute excitotoxic injury to the hippocampus is the finding that systemic exposure to MK-801, an antagonist at the NMDA receptor, inhibits hippocampal tau phosphorylation after noise exposure (Li et al, 2014).…”

Section: Noise Exposure and Hippocampal Tissue Healthmentioning

confidence: 86%

Does hearing loss lead to dementia? A review of the literature

Nadhimi

Llano

2021

Hearing Research

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Recent studies have revealed a correlation between aging-related hearing loss and the likelihood of developing Alzheimer Disease. However, it is not yet known if the correlation simply reflects the fact that these two disorders share common risk factors or whether there is a causal link between them. The answer to this question carries therapeutic implications. Unfortunately, it is not possible to study the question of causality between aging-related hearing loss and dementia in human subjects. Here, we evaluate the research surrounding induced-hearing loss in animal models on non-auditory cognition to help infer if there is any causal evidence linking hearing loss and a more general dementia. We find ample evidence that induction of hearing loss in animals produces cognitive decline, particularly hippocampal dysfunction. The data suggest that noiseexposure produces a toxic milieu in the hippocampus consisting of a spike in glucocorticoid levels, elevations of mediators of oxidative stress and excitotoxicity, which as a consequence induce cessation of neurogenesis, synaptic loss and tau hyperphosphorylation. These data suggest that hearing loss can lead to pathological hallmarks similar to those seen in Alzheimer's Disease and other dementias. However, the rodent data do not establish that hearing loss on its own can induce a progressive degenerative dementing illness. Therefore, we conclude that an additional "hit", such as aging, APOE genotype, microvascular disease or others, may be necessary to trigger an ongoing degenerative process such as Alzheimer Disease.

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Section: Noise Exposure and Hippocampal Tissue Healthmentioning

confidence: 86%

Does hearing loss lead to dementia? A review of the literature

Nadhimi

Llano

2021

Hearing Research

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“…For example, (1) insulin receptors (IRs) in the brain have been shown to be downregulated in AD models [8]; (2) the impairment of insulin signaling has been documented in the brain from both postmortem analysis of AD patients and in animal models of AD [6][7][8][9]; and (3) the deficit of memory function in AD patients has been shown to be associated with altered levels of circulating insulin, insulin levels in the brain, and defects in peripheral insulin signaling pathways [4,5,10]. It is well known that insulin signaling is associated with the regulation of tau protein, and deregulation of brain insulin signaling is linked to AD [12]. For example, systemic insulin resistance results in tau hyperphosphorylation detected in cerebrospinal fluid [13].…”

Section: Introductionmentioning

confidence: 99%

Liraglutide Suppresses Tau Hyperphosphorylation, Amyloid Beta Accumulation through Regulating Neuronal Insulin Signaling and BACE-1 Activity

Jantrapirom

Nimlamool

Chattipakorn

et al. 2020

IJMS

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Neuronal insulin resistance is a significant feature of Alzheimer’s disease (AD). Accumulated evidence has revealed the possible neuroprotective mechanisms of antidiabetic drugs in AD. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog and an antidiabetic agent, has a benefit in improving a peripheral insulin resistance. However, the neuronal effect of liraglutide on the model of neuronal insulin resistance with Alzheimer’s formation has not been thoroughly investigated. The present study discovered that liraglutide alleviated neuronal insulin resistance and reduced beta-amyloid formation and tau hyperphosphorylation in a human neuroblostoma cell line, SH-SY5Y. Liraglutide could effectively reverse deleterious effects of insulin overstimulation. In particular, the drug reversed the phosphorylation status of insulin receptors and its major downstream signaling molecules including insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK-3β). Moreover, liraglutide reduced the activity of beta secretase 1 (BACE-1) enzyme, which then decreased the formation of beta-amyloid in insulin-resistant cells. This indicated that liraglutide can reverse the defect of phosphorylation status of insulin signal transduction but also inhibit the formation of pathogenic Alzheimer’s proteins like Aβ in neuronal cells. We herein provided the possibility that the liraglutide-based therapy may be able to reduce such deleterious effects caused by insulin resistance. In view of the beneficial effects of liraglutide administration, these findings suggest that the use of liraglutide may be a promising therapy for AD with insulin-resistant condition.

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“…Conversely, hypothalamic soluble Aβ and Tau phosphorylation may contribute to the impairment of the control of peripheral glucose metabolism in patients with AD (Cai, 2013; Chen and Zhong, 2013). This could be mediated by a direct effect of Aβ on central IR and by a mechanism mediated by Tau hyperphosphorylation, which increases intraneuronal insoluble insulin aggregates and downregulates IRs, leading to insulin resistance (El Khoury et al, 2014; Marciniak et al, 2017; Rodriguez-Rodriguez et al, 2017; Gonçalves et al, 2019).…”

Section: Which Came First: Obesity or Aβ? The “Chicken Or The Egg” Camentioning

confidence: 99%

The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer’s Dementia

Folch

Olloquequi

Ettcheto

et al. 2019

Front. Aging Neurosci.

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Nowadays, Alzheimer’s disease (AD) is a severe sociological and clinical problem. Since it was first described, there has been a constant increase in its incidence and, for now, there are no effective treatments since current approved medications have only shown short-term symptomatic benefits. Therefore, it is imperative to increase efforts in the search for molecules and non-pharmacological strategies that are capable of slowing or stopping the progress of the disease and, ideally, to reverse it. The amyloid cascade hypothesis based on the fundamental role of amyloid has been the central hypothesis in the last 30 years. However, since amyloid-directed treatments have shown no relevant beneficial results other theories have been postulated to explain the origin of the pathology. The brain is a highly metabolically active energy-consuming tissue in the human body. It has an almost complete dependence on the metabolism of glucose and uses most of its energy for synaptic transmission. Thus, alterations on the utilization or availability of glucose may be cause for the appearance of neurodegenerative pathologies like AD. In this review article, the hypothesis known as Type 3 Diabetes (T3D) will be evaluated by summarizing some of the data that has been reported in recent years. According to published research, the adherence over time to low saturated fatty acids diets in the context of the Mediterranean diet would reduce the inflammatory levels in brain, with a decrease in the pro-inflammatory glial activation and mitochondrial oxidative stress. In this situation, the insulin receptor pathway would be able to fine tune the mitochondrial biogenesis in neuronal cells, regulation the adenosine triphosphate/adenosine diphosphate intracellular balance, and becoming a key factor involved in the preservation of the synaptic connexions and neuronal plasticity. In addition, new targets and strategies for the treatment of AD will be considered in this review for their potential as new pharmacological or non-pharmacological approaches.

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The Link Between Tau and Insulin Signaling: Implications for Alzheimer’s Disease and Other Tauopathies

Cited by 66 publications

References 84 publications

Does hearing loss lead to dementia? A review of the literature

Does hearing loss lead to dementia? A review of the literature

Liraglutide Suppresses Tau Hyperphosphorylation, Amyloid Beta Accumulation through Regulating Neuronal Insulin Signaling and BACE-1 Activity

The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer’s Dementia

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