d6bd97d028d52c149589da975ec49c8c pmc_29382127.pdf d789388a83d52d0e3f849462cf7a53fdbd3be35c pmc_29382127.pdf 08e3a53f6bd41dd48fa3743443375db0eba417912e94034e7d89b844741b8dcd pmc_29382127.pdf Title: The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia Subject: Alzheimer’s disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid peptide (A), 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 A 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 A42 generated in the brain would impact negatively on the hypothalamus, accelerating the “peripheral” symptomatology of AD. In this situation, A42 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. Keywords: Alzheimer’s; insulin resistance; amyloid; TAU; cognition; insulin receptor; type 2 diabetes Author: Jaume Folch, Miren Ettcheto, Oriol Busquets, Elena Sánchez-López, Rubén D. Castro-Torres, Ester Verdaguer, Patricia R. Manzine, Saghar Rabiei Poor, María Luisa García, Jordi Olloquequi, Carlos Beas-Zarate, Carme Auladell and Antoni Camins Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.15 CreationDate: Mon Jan 29 08:24:51 2018 CET ModDate: Mon Jan 29 08:24:51 2018 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 942409 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ZVKLZB+URWPalladioL-Ital Type 1 Custom yes yes no 68 0 XKVSXB+URWPalladioL-Bold Type 1 Custom yes yes no 69 0 JYPLJJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 70 0 GLESUF+URWPalladioL-Roma Type 1 Custom yes yes no 71 0 QOATDH+VnURWPalladioL Type 1 Custom yes yes no 72 0 BIFPKP+CMSY10 Type 1 Builtin yes yes no 73 0 CHMOKT+EURM10 Type 1 Builtin yes yes no 74 0 VWRBXB+TimesNewRomanPS-BoldItalicMT Type 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