Evidence for altered insulin receptor signaling in Alzheimer's disease

Griffith, Chelsea M.; Eid, Tore; Rose, Gregory M.; Patrylo, Peter R.

doi:10.1016/j.neuropharm.2018.01.008

Cited by 48 publications

(27 citation statements)

References 204 publications

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“…Many studies indicate that insulin signaling plays a significant role in AD [ 21 , 22 ]. The diminished utilization of glucose by the brain during AD leads to reduced neuronal signal transmission and impaired cognitive abilities [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Gamma radiation improves AD pathogenesis in APP/PS1 mouse model by potentiating insulin sensitivity

Khandelwal

Manglani

Gupta

et al. 2020

Heliyon

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Alzheimer's disease (AD) is the largest unmet medical complication. The devastation caused by the disease can be assumed from the disease symptoms like speech impairment, loss of self-awareness, acute memory loss etc. The individuals suffering from AD completely depend on caregivers and have to bear the high cost of treatment which increases the socio-economic burden on the society. Recent studies have shown that radiation exposure can have therapeutic effects when given in suitable amount for a specific time period. Therefore, we investigated the role of gamma irradiation in AD pathogenesis. The effect of radiation on amelioration of disease progression was studied in AD transgenic mice model (APP/PS1). Our in-vivo studies using APP/PS1 mice demonstrated that a single dose of 4.0 Gy gamma irradiation improves AD associated behavioral impairment. Radiation exposure also increased the level of anti-oxidant enzymes and reduced the astrocyte activation in the brain of APP/PS1 mice. A significant reduction was observed in AD associated proteins (APP, pTau, BACE) and neurofibrillary tangle formations (NFTs). Exposure to a single dose of 4 Gy gamma radiation also increased glucose metabolic functionality in AD transgenic mouse model. The kinases involved in insulin signaling such as GSK, ERK and JNK were also found to be modulated. However, an increased level of GSK3β (ser 9) was observed, which could be responsible for downregulating ERK and JNK phosphorylation. This resulted in a decrease in neurofibrillary tangle formations and amyloid deposition. The reduced hyperphosphorylation of Tau can be attributed to the increased level of GSK3β (ser 9) downregulating ERK and JNK phosphorylation. Thus, a single dose of 4 Gy gamma irradiation was found to have therapeutic benefits in treating AD via potentiating insulin signaling in APP/PS1 transgenic mice.

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Section: Discussionmentioning

confidence: 99%

Gamma radiation improves AD pathogenesis in APP/PS1 mouse model by potentiating insulin sensitivity

Khandelwal

Manglani

Gupta

et al. 2020

Heliyon

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“…Impairment of CNS insulin signaling is due to decrease in brain insulin levels, e.g., due to decreased peripheral production or altered capacity for insulin to cross the blood-brain barrier (BBB), or a change in CNS insulin receptor (IR) sensitivity (e.g., IR desensitization due to elevated insulin levels). IRs is differentially expressed in various parts of brain like hippocampus, hypothalamus, cerebral cortex, and amygdala [54]. Under normal physiological conditions when insulin binds to the IR, a cascade regulates key downstream serine/threonine kinases such as, protein kinases B (AKT/PKB), mechanistic target of rapamycin (mTOR), and extracellular signal-regulated kinases (ERK) that eventually phosphorylate serine/threonine residues of insulin receptor substrate (IRS), and inhibiting insulin signaling in a negative feedback regulation.…”

Section: Insulin Desensitization and Tau Hyperphosphorylationmentioning

confidence: 99%

“…OKA, a polyether C38 fatty acid extracted from a black sponge, Hallichondria okadaii, has been extensively used, since it is a potent and selective inhibitor of the serine/threonine phosphatases 1 (PP1) and 2A (PP2A) and also, although at higher concentrations, of the Ca 2+ /calmodulindependent PP2B (calcineurin) [93,106,107]. The reduced activity of PP2A has been linked with the pathology of AD and was supposed to be involved in hyperphosphorylation of tau [54]. ICVOKA injection develops memory impairment in rats, making it suitable for identification as a potential AD model.…”

Section: The Okadaic Acid Modelmentioning

confidence: 99%

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

Duggal

Mehan

2019

ADR

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Neuronal microtubule (MT) tau protein provides cytoskeleton to neuronal cells and plays a vital role including maintenance of cell shape, intracellular transport, and cell division. Tau hyperphosphorylation mediates MT destabilization resulting in axonopathy and neurotransmitter deficit, and ultimately causing Alzheimer's disease (AD), a dementing disorder affecting vast geriatric populations worldwide, characterized by the existence of extracellular amyloid plaques and intracellular neurofibrillary tangles in a hyperphosphorylated state. Pre-clinically, streptozotocin stereotaxically mimics the behavioral and biochemical alterations similar to AD associated with tau pathology resulting in MT assembly defects, which proceed neuropathological cascades. Accessible interventions like cholinesterase inhibitors and NMDA antagonist clinically provides only symptomatic relief. Involvement of microtubule stabilizers (MTS) prevents tauopathy particularly by targeting MT oriented cytoskeleton and promotes polymerization of tubulin protein. Multiple in vitro and in vivo research studies have shown that MTS can hold substantial potential for the treatment of AD-related tauopathy dementias through restoration of tau function and axonal transport. Moreover, anti-cancer taxane derivatives and epothiolones may have potential to ameliorate MT destabilization and prevent the neuronal structural and functional alterations associated with tauopathies. Therefore, this current review strictly focuses on exploration of various clinical and pre-clinical features available for AD to understand the neuropathological mechanisms as well as introduce pharmacological interventions associated with MT stabilization. MTS from diverse natural sources continue to be of value in the treatment of cancer, suggesting that these agents have potential to be of interest in the treatment of AD-related tauopathy dementia in the future.

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“…Alzheimer's disease (AD) is the most common cause of dementia in elderly humans [18]. On the other hand, not only is the CNS involved in the manifestation of the illness, but several other disorders are associated with it, such as diabetes [19], vascular abnormalities [20] and inflammation [21]. AD is investigated mainly in the CNS, but it is shown to be a systemic disease with several pathological alterations in the periphery [21].…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s Disease Mouse as a Model of Testis Degeneration

Szegeczki

Horváth

Perényi

et al. 2020

IJMS

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Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with protective functions in the central nervous system and various peripheral organs. PACAP has the highest expression level in the testes, among the peripheral organs, and has a positive regulative role in spermatogenesis and in sperm motility. In the present study, we explored testicular degenerative alterations in a mouse model of Alzheimer’s disease (AD) (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) and demonstrated changes in PACAP-regulated signaling pathways. In addition, the effects of increased physical activity of AD (trained AD (TAD)) mice on testis were also followed. Reduced cell number and decreased thickness of basement membrane were detected in AD samples. These changes were compensated by physical activity. Expression of PACAP receptors and canonical signaling elements such as PKA, P-PKA, PP2A significantly decreased in AD mice, and altered Sox transcription factor expression was also detected. Via this signaling mechanism, physical activity compensated the negative effects of AD on the expression of type IV collagen. Our findings suggest that the testes of AD mice can be a good model of testis degeneration. Moreover, it can be an appropriate organ to follow the effects of various interventions such as physical activity on tissue regeneration and signaling alterations.

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Evidence for altered insulin receptor signaling in Alzheimer's disease

Cited by 48 publications

References 204 publications

Gamma radiation improves AD pathogenesis in APP/PS1 mouse model by potentiating insulin sensitivity

Gamma radiation improves AD pathogenesis in APP/PS1 mouse model by potentiating insulin sensitivity

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

Alzheimer’s Disease Mouse as a Model of Testis Degeneration

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