PMID- 34577590 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20211001 IS - 1424-8247 (Print) IS - 1424-8247 (Electronic) IS - 1424-8247 (Linking) VI - 14 IP - 9 DP - 2021 Sep 1 TI - Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer's Disease Treatment. LID - 10.3390/ph14090890 [doi] LID - 890 AB - 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. FAU - Poor, Saghar Rabiei AU - Poor SR AD - Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran. AD - Institute for Brain and Cognition, Tarbiat Modares University, Tehran 14117-13116, Iran. AD - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociencies, University of Barcelona, 08028 Barcelona, Spain. FAU - Ettcheto, Miren AU - Ettcheto M AUID- ORCID: 0000-0002-4301-7297 AD - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociencies, University of Barcelona, 08028 Barcelona, Spain. AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 08028 Madrid, Spain. FAU - Cano, Amanda AU - Cano A AUID- ORCID: 0000-0001-9567-4283 AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 08028 Madrid, Spain. AD - Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08028 Barcelona, Spain. AD - Institute of Nanoscience and Nanotechnology (IN2UB), 08028 Barcelona, Spain. AD - Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain. FAU - Sanchez-Lopez, Elena AU - Sanchez-Lopez E AUID- ORCID: 0000-0003-2571-108X AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 08028 Madrid, Spain. AD - Institute of Nanoscience and Nanotechnology (IN2UB), 08028 Barcelona, Spain. AD - Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain. FAU - Manzine, Patricia Regina AU - Manzine PR AUID- ORCID: 0000-0003-3460-9300 AD - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociencies, University of Barcelona, 08028 Barcelona, Spain. AD - Department of Gerontology, Federal University of Sao Carlos (UFSCar), Sao Carlos 13565-905, Brazil. FAU - Olloquequi, Jordi AU - Olloquequi J AD - Laboratory of Cellular and Molecular Pathology, Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autonoma de Chile, Talca 3467987, Chile. FAU - Camins, Antoni AU - Camins A AUID- ORCID: 0000-0002-1229-5956 AD - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociencies, University of Barcelona, 08028 Barcelona, Spain. AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 08028 Madrid, Spain. AD - Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08028 Barcelona, Spain. AD - Laboratory of Cellular and Molecular Pathology, Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autonoma de Chile, Talca 3467987, Chile. FAU - Javan, Mohammad AU - Javan M AUID- ORCID: 0000-0003-2045-6171 AD - Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran. AD - Institute for Brain and Cognition, Tarbiat Modares University, Tehran 14117-13116, Iran. AD - Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14117-13116, Iran. LA - eng PT - Journal Article PT - Review DEP - 20210901 PL - Switzerland TA - Pharmaceuticals (Basel) JT - Pharmaceuticals (Basel, Switzerland) JID - 101238453 PMC - PMC8465337 OTO - NOTNLM OT - AMP activated protein kinase (AMPK) OT - Alzheimer's disease OT - beta amyloid OT - diabetes mellitus OT - insulin resistance OT - metformin OT - tau protein hyperphosphorylation COIS- The authors declare no conflict of interest. EDAT- 2021/09/29 06:00 MHDA- 2021/09/29 06:01 PMCR- 2021/09/01 CRDT- 2021/09/28 01:23 PHST- 2021/07/12 00:00 [received] PHST- 2021/08/23 00:00 [revised] PHST- 2021/08/28 00:00 [accepted] PHST- 2021/09/28 01:23 [entrez] PHST- 2021/09/29 06:00 [pubmed] PHST- 2021/09/29 06:01 [medline] PHST- 2021/09/01 00:00 [pmc-release] AID - ph14090890 [pii] AID - pharmaceuticals-14-00890 [pii] AID - 10.3390/ph14090890 [doi] PST - epublish SO - Pharmaceuticals (Basel). 2021 Sep 1;14(9):890. doi: 10.3390/ph14090890.