Studies have shown that brain insulin resistance causes accumulation of Aβ which increases cytokine production [125, 131]. Amyloid precursor protein (APP) is a precursor molecule whose proteolysis generates Aβ and it is found in the nerve cell membrane [138, 139]. In a number of studies, abnormal insulin and IGF protein levels and their receptors, which is the main characteristic of brain insulin resistance or T3DM, is thought to be involved in Aβ accumulation and Aβ clearance [140, 141] which promotes neuroinflammation leading to memory impairment and giving the pathophysiological characteristics of AD [115, 124, 142]. Moreover, abnormal expression of insulin and IGF proteins and their receptors activates the RAGE-Aβ interaction which mediates pro-inflammatory responses [143-145]. Neuro-inflammation starts a pro-inflammatory cascade that causes neurotoxic substances to release, including cytokines, chemokines, reactive oxygen and nitrogen species, and various proteolytic enzymes which cause sustained activation of microglia and astrocyte in the brain . These results demonstrate that over time inflammation can be a consequences of brain insulin resistance which enhances the accumulation of Aβ
Tau proteins are proteins that stabilize microtubules. They are abundant in the neurons of the central nervous system . In healthy brains, insulin and IGF regulate tau gene expression and phosphorylation . Amongst Alzheimer disease patients, tau hyperphosphorylation increases the activation of Glycogen synthase kinase 3 beta (GSK-3B) signaling which lowers insulin and IGF levels in the brain which is a characteristic of brain insulin resistance [148-150]. It has been reported that...
... middle of paper ...
...in may cross the blood brain barrier, thus it does not depend on separate control of insulin production in the brain as proposed by De la Monte.
Even though there are still some misunderstandings and gaps in our knowledge about brain insulin resistance, based on the evidence mentioned, inflammation has a synergistic effect on brain insulin resistance (T3DM) as both cause and a consequence, as seen in (Fig 4). Insulin resistance causes vascular dysfunction and dyslipidemia, which increases inflammatory biomarkers and Aβ production in both the periphery and the central nervous system (CNS). Over time, this action contributes to the progression of AD and brain insulin resistance. Concomitantly, high levels of inflammatory mediators in AD can be consequences of brain insulin resistance (T3DM), due to the high levels of Aβ, tau proteins, and ROS production in the brain.
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