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The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

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  • The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

    Pharmaceuticals2018, 11(1), 11; doi:10.3390/ph11010011

    Published: 29 January 2018

    Abstract

    Alzheimer’s disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis.

    Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Aβ production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD) pathogenesis, more data is being obtained. Recent evidence showed that Aβ42 generated in the brain would impact negatively on the hypothalamus, accelerating the “peripheral” symptomatology of AD.

    In this situation, Aβ42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD.

    Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors.


    ................................................


    9. Conclusions

    Given the amount of data of which we are in possession now, it can be concluded that the pathology hereby described as LOAD is very closely related to the alterations derived of insulin resistance. Effective energy metabolism is the base on the proper functioning of cellular types and, when disrupted, affects negatively their function. In the case of neurons, which are having glucose as its main energy source, this situation can be utterly disastrous leading to their ineffective activity and consequently cognitive decline. That is why the IR has such a prominent role.
    It is now well established Aβ could bind to the IR in the hippocampus, revealing important cognitive loss, when the receptor is inhibited and enhancing the neurodegenerative process in this brain region. Moreover, Aβ bind to the liver IR in the preclinical APPswe/PS1E9 mice model of familial AD, suggesting the possibility that decreases of Aβ production may be a novel potential treatment for use in T2DM (Figure 2) [73,74,112]. Lastly, the therapeutic potential of Aβ inhibitors (for example BACE 1 inhibitors) has not yet been verified in clinical trials.

    However, antidiabetic therapies such as pioglitazone or intranasal insulin are more likely to be effective in individuals with LOAD. Therefore, we suggest that the future timing of a more effective LOAD therapy should be the key factor in determining if T2DM drugs shown beneficial actions in LOAD. Targeting the early stages of LOAD, before widespread cognitive loss due to synapses and neurons degeneration has occurred is likely to produce the best clinical outcome, but identification of individuals at this stage of LOAD is difficult.

    Accordingly, the modulation of brain IR preventing its inactivation could be a suitable strategy in a combinatory strategy therapy for LOAD.

    Alzheimer’s disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Aβ production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD) pathogenesis, more data is being obtained. Recent evidence showed that Aβ42 generated in the brain would impact negatively on the hypothalamus, accelerating the “peripheral” symptomatology of AD. In this situation, Aβ42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors.
    “Addressing chronic disease is an issue of human rights – that must be our call to arms"
    Richard Horton, Editor-in-Chief The Lancet

    ~~~~ Twitter:@GertvanderHoek ~~~ GertvanderHoek@gmail.com ~~~
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