6ce10eea8c84107c66dd7b4fe37d96e2 pmc_34577590.pdf 302e1b4b3df71302aff5ff3daef31e2d7bc8f203 pmc_34577590.pdf 2d74c156bed2883f53ad1b0fc3a11ad9dd39b1a840a34a0f4a4b027a6f46ab66 pmc_34577590.pdf Title: Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment Subject: Alzheimer’s disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to “type 3 diabetes” and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with positive and negative findings. In spite of this, metformin shows positive benefits such as anti-inflammatory effects, accelerated neurogenesis, strengthened memory, and prolonged life expectancy. Moreover, it has been recently demonstrated that metformin enhances synaptophysin, sirtuin-1, AMPK, and brain-derived neuronal factor (BDNF) immunoreactivity, which are essential markers of plasticity. The present review discusses the numerous studies which have explored (1) the neuropathological hallmarks of AD, (2) association of type 2 diabetes with AD, and (3) the potential therapeutic effects of metformin on AD and preclinical models. Keywords: Alzheimer’s disease; diabetes mellitus; metformin; insulin resistance; beta amyloid; tau protein hyperphosphorylation; AMP activated protein kinase (AMPK) Author: Saghar Rabiei Poor, Miren Ettcheto, Amanda Cano, Elena Sanchez-Lopez, Patricia Regina Manzine, Jordi Olloquequi, Antoni Camins and Mohammad Javan Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Sep 1 11:00:19 2021 CEST ModDate: Wed Sep 1 11:22:33 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 22 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 766832 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- TFSDOV+VnURWPalladioL Type 1 Custom yes yes no 10 0 IPCXZV+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 VNALLM+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 YPWHDF+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 SAUAIP+CMSY10 Type 1 Builtin yes yes no 28 0 VWRBXB+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 36 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 58 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 62 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 66 0 VFLYPI+EURM10 Type 1 Builtin yes yes no 78 0 GHEIHN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 128 0 GHEIHO+PalatinoLinotype CID TrueType Identity-H yes yes yes 131 0 GHEIHP+PalatinoLinotype TrueType WinAnsi yes yes no 137 0 GHEIIB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 140 0 WBREXZ+PazoMath-Italic Type 1 Builtin yes yes no 148 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-03-22 02:44:15 CET RepresentationInformation: pmc_34577590.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2021-10-04 03:35:42 CEST Size: 766832 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 746 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Type 2 Diabetes Mellitus Related with Alzheimer’s Disease Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Metformin as an Antidiabetic Drug Strategy for Alzheimer’s Disease Treatment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Children: Item: Title: Preclinical Animal Studies with Metformin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Metformin in Clinical Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Molecular Mechanism Involved in Neuroprotective Effects of Metformin in Alzheimer’s Disease Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Metformin Effects on Amyloid and Tau Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Metformin Effects on Mitochondria Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Metformin Effects on Neurogenesis: The AMPK/aPKC/CBP Signaling Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Metformin Effects on Learning and Memory Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Metformin Effects on Synaptic Density and Dendritic Spines Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Metformin Effects on Neuroinflammation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Neuroprotective and Neurorestorative Potential of Metformin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Info: Title: Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment Author: Saghar Rabiei Poor, Miren Ettcheto, Amanda Cano, Elena Sanchez-Lopez, Patricia Regina Manzine, Jordi Olloquequi, Antoni Camins and Mohammad Javan Subject: Alzheimer’s disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to “type 3 diabetes” and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with positive and negative findings. In spite of this, metformin shows positive benefits such as anti-inflammatory effects, accelerated neurogenesis, strengthened memory, and prolonged life expectancy. Moreover, it has been recently demonstrated that metformin enhances synaptophysin, sirtuin-1, AMPK, and brain-derived neuronal factor (BDNF) immunoreactivity, which are essential markers of plasticity. The present review discusses the numerous studies which have explored (1) the neuropathological hallmarks of AD, (2) association of type 2 diabetes with AD, and (3) the potential therapeutic effects of metformin on AD and preclinical models. 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