Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer's disease

Akhtar, Ansab; Sah, Sangeeta Pilkhwal

doi:10.1016/j.neuint.2020.104707

Cited by 160 publications

(116 citation statements)

References 159 publications

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“…That the sIPSCs amplitudes and densities were decreased in the aged tg‐APPSwe mice relative to the aged wild‐type littermates, implies a general decrease in the number of postsynaptic GABA A receptors in the DG granule cells in the aged tg‐APPSwe animals or, alternatively, decreased release of GABA from the presynaptic terminals. It is possible that the increased tonic current that was normalized by insulin is related, in part, to the synaptic‐type receptors remaining outside of synapses in the aged tg‐APPSwe mice but then, are rescued by insulin, resulting in normalized and increased synaptic and decreased extrasynaptic current densities 72‐74 . Notably, the DG granule cells are clearly not insulin resistant in the presence of amyloid pathology.…”

Section: Discussionmentioning

confidence: 99%

Insulin differentially modulates GABA signalling in hippocampal neurons and, in an age‐dependent manner, normalizes GABA‐activated currents in the tg‐APPSwe mouse model of Alzheimer’s disease

et al. 2021

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Aim We examined if tonic γ‐aminobutyric acid (GABA)‐activated currents in primary hippocampal neurons were modulated by insulin in wild‐type and tg‐APPSwe mice, an Alzheimer's disease (AD) model. Methods GABA‐activated currents were recorded in dentate gyrus (DG) granule cells and CA3 pyramidal neurons in hippocampal brain slices, from 8 to 10 weeks old (young) wild‐type mice and in dorsal DG granule cells in adult, 5‐6 and 10‐12 (aged) months old wild‐type and tg‐APPSwe mice, in the absence or presence of insulin, by whole‐cell patch‐clamp electrophysiology. Results In young mice, insulin (1 nmol/L) enhanced the total spontaneous inhibitory postsynaptic current (sIPSCT) density in both dorsal and ventral DG granule cells. The extrasynaptic current density was only increased by insulin in dorsal CA3 pyramidal neurons. In absence of action potentials, insulin enhanced DG granule cells and dorsal CA3 pyramidal neurons miniature IPSC (mIPSC) frequency, consistent with insulin regulation of presynaptic GABA release. sIPSCT densities in DG granule cells were similar in wild‐type and tg‐APPSwe mice at 5‐6 months but significantly decreased in aged tg‐APPSwe mice where insulin normalized currents to wild‐type levels. The extrasynaptic current density was increased in tg‐APPSwe mice relative to wild‐type littermates but, only in aged tg‐APPSwe mice did insulin decrease and normalize the current. Conclusion Insulin effects on GABA signalling in hippocampal neurons are selective while multifaceted and context‐based. Not only is the response to insulin related to cell‐type, hippocampal axis‐location, age of animals and disease but also to the subtype of neuronal inhibition involved, synaptic or extrasynaptic GABAA receptors‐activated currents.

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Section: Discussionmentioning

confidence: 99%

Insulin differentially modulates GABA signalling in hippocampal neurons and, in an age‐dependent manner, normalizes GABA‐activated currents in the tg‐APPSwe mouse model of Alzheimer’s disease

et al. 2021

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“…Dysfunctional insulin signaling has been linked to the pathogenesis of aggregated tau neurofibrillary tangles, a major neuropathological hallmark of AD [ 58 , 59 ]. Individuals with glaucoma have been found to have hyperphosphorylated tau in their CSF and ocular samples [ 60 , 61 , 62 ].…”

Section: Influence Of Insulin Signaling On Glaucoma Pathogenesismentioning

confidence: 99%

“…A clinical trial investigating the effect of metformin on visual function in patients with glaucoma (ClinicalTrials.gov: NCT04155164) is currently recruiting patients. Pre-clinical and clinical studies of the use of other anti-glycemic agents such as thiazolidinediones and GLP-1 analogs in AD and PD also provide promising results [ 59 , 77 ]. Given the epidemiologic and pathologic association between neurodegenerative disease of the CNS and T2DM, anti-glycemic agents are a potential novel treatment option in the management of glaucoma.…”

Section: Targeting Insulin Resistance Therapeutically In Neurodegenerationmentioning

confidence: 99%

Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration

Wareham

Risner

Calkins

2021

IJMS

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Glaucoma is a multifactorial disease that is conventionally managed with treatments to lower intraocular pressure (IOP). Despite these efforts, many patients continue to lose their vision. The degeneration of retinal ganglion cells (RGCs) and their axons in the optic tract that characterizes glaucoma is similar to neurodegeneration in other age-related disorders of the central nervous system (CNS). Identifying the different molecular signaling pathways that contribute to early neuronal dysfunction can be utilized for neuroprotective strategies that prevent degeneration. The discovery of insulin and its receptor in the CNS and retina led to exploration of the role of insulin signaling in the CNS. Historically, insulin was considered a peripherally secreted hormone that regulated glucose homeostasis, with no obvious roles in the CNS. However, a growing number of pre-clinical and clinical studies have demonstrated the potential of modulating insulin signaling in the treatment of neurodegenerative diseases. This review will highlight the role that insulin signaling plays in RGC neurodegeneration. We will focus on how this pathway can be therapeutically targeted to promote RGC axon survival and preserve vision.

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“…Cerebral insulin resistance has been accepted as contributing to the neurodegenerative process in AD by activating oxidative stress, cytokine production, and apoptotic process [41]. It is also the link between sporadic AD and its risk factor of diabetes [42].…”

Section: Pathophysiological Hypotheses and Associated Biomarkersmentioning

confidence: 99%

Utility of Animal Models to Understand Human Alzheimer’s Disease, Using the Mastermind Research Approach to Avoid Unnecessary Further Sacrifices of Animals

Qin

Prins

Groeneveld

et al. 2020

IJMS

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To diagnose and treat early-stage (preclinical) Alzheimer’s disease (AD) patients, we need body-fluid-based biomarkers that reflect the processes that occur in this stage, but current knowledge on associated processes is lacking. As human studies on (possible) onset and early-stage AD would be extremely expensive and time-consuming, we investigate the potential value of animal AD models to help to fill this knowledge gap. We provide a comprehensive overview of processes associated with AD pathogenesis and biomarkers, current knowledge on AD-related biomarkers derived from on human and animal brains and body fluids, comparisons of biomarkers obtained in human AD and frequently used animal AD models, and emerging body-fluid-based biomarkers. In human studies, amyloid beta (Aβ), hyperphosphorylated tau (P-tau), total tau (T-tau), neurogranin, SNAP-25, glial fibrillary acidic protein (GFAP), YKL-40, and especially neurofilament light (NfL) are frequently measured. In animal studies, the emphasis has been mostly on Aβ. Although a direct comparison between human (familial and sporadic) AD and (mostly genetic) animal AD models cannot be made, still, in brain, cerebrospinal fluid (CSF), and blood, a majority of similar trends are observed for human AD stage and animal AD model life stage. This indicates the potential value of animal AD models in understanding of the onset and early stage of AD. Moreover, animal studies can be smartly designed to provide mechanistic information on the interrelationships between the different AD processes in a longitudinal fashion and may also include the combinations of different conditions that may reflect comorbidities in human AD, according to the Mastermind Research approach.

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Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer's disease

Cited by 160 publications

References 159 publications

Insulin differentially modulates GABA signalling in hippocampal neurons and, in an age‐dependent manner, normalizes GABA‐activated currents in the tg‐APPSwe mouse model of Alzheimer’s disease

Insulin differentially modulates GABA signalling in hippocampal neurons and, in an age‐dependent manner, normalizes GABA‐activated currents in the tg‐APPSwe mouse model of Alzheimer’s disease

Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration

Utility of Animal Models to Understand Human Alzheimer’s Disease, Using the Mastermind Research Approach to Avoid Unnecessary Further Sacrifices of Animals

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