PMID- 34311050
OWN - NLM
STAT- MEDLINE
DCOM- 20220120
LR  - 20220120
IS  - 1872-7972 (Electronic)
IS  - 0304-3940 (Linking)
VI  - 762
DP  - 2021 Sep 25
TI  - Metformin attenuates vascular pathology by increasing expression of 
      insulin-degrading enzyme in a mixed model of cerebral amyloid angiopathy and type 
      2 diabetes mellitus.
PG  - 136136
LID - S0304-3940(21)00514-0 [pii]
LID - 10.1016/j.neulet.2021.136136 [doi]
AB  - Sporadic cerebral amyloid angiopathy (CAA), which is characterized by 
      cerebrovascular amyloid beta (Abeta) deposits, causes cerebral hemorrhages and dementia 
      in elderly people. Metformin has been used to treat patients with type 2 diabetes 
      mellitus (T2DM), and animal and clinical studies have reported therapeutic 
      effects of metformin in Alzheimer's disease (AD). However, the therapeutic 
      effects of metformin in CAA are unclear. Here, we used a mixed mouse model of CAA 
      and T2DM (APP23-ob/ob) to investigate whether metformin has therapeutic effects 
      on cerebrovascular Abeta deposits. We dissolved metformin hydrochloride in water and 
      administered it orally at 350 mg/kg/day. Treatments started when mice were 
      6 weeks old and continued until they were 15 months old. After we treated 
      APP23-ob/ob mice with metformin, we counted the numbers of vessels with Abeta and 
      measured levels of Abeta40 and Abeta42 (soluble and insoluble), amyloid precursor 
      protein (APP), APP-processing enzymes (alpha-, beta-, and gamma-secretases), and 
      Abeta-degrading enzymes (insulin-degrading enzyme [IDE], neprilysin). Metformin 
      significantly reduced cerebrovascular Abeta deposits in APP23-ob/ob mice (p < .05). 
      Compared with controls, metformin-treated APP23-ob/ob mice had significantly 
      reduced Abeta levels in the cerebral cortex (p < .05) and hippocampus (p < .05) and 
      increased levels of IDE in the hippocampus (p < .01). Our results indicate that 
      metformin attenuates the severity of CAA by enhancing Abeta-cleaving IDE expression. 
      The clinical application of metformin may lead to a novel therapeutic strategy in 
      CAA treatment, especially in patients with T2DM.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Inoue, Yasuteru
AU  - Inoue Y
AD  - Department of Neurology, Graduate School of Medical Sciences, Kumamoto 
      University, Kumamoto, Japan. Electronic address: yinoue@kuh.kumamoto-u.ac.jp.
FAU - Masuda, Teruaki
AU  - Masuda T
AD  - Department of Neurology, Graduate School of Medical Sciences, Kumamoto 
      University, Kumamoto, Japan.
FAU - Misumi, Yohei
AU  - Misumi Y
AD  - Department of Neurology, Graduate School of Medical Sciences, Kumamoto 
      University, Kumamoto, Japan.
FAU - Ando, Yukio
AU  - Ando Y
AD  - Department of Amyloidosis Research, Nagasaki International University, Sasebo, 
      Japan.
FAU - Ueda, Mitsuharu
AU  - Ueda M
AD  - Department of Neurology, Graduate School of Medical Sciences, Kumamoto 
      University, Kumamoto, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210724
PL  - Ireland
TA  - Neurosci Lett
JT  - Neuroscience letters
JID - 7600130
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Hypoglycemic Agents)
RN  - 9100L32L2N (Metformin)
RN  - EC 3.4.24.56 (Insulysin)
SB  - IM
MH  - Amyloid beta-Peptides/metabolism
MH  - Animals
MH  - Cerebral Amyloid Angiopathy/complications/*pathology
MH  - Cerebrovascular Circulation/drug effects
MH  - Diabetes Mellitus, Experimental/*pathology
MH  - Diabetes Mellitus, Type 2/*complications
MH  - Hypoglycemic Agents/*pharmacology
MH  - Insulysin/*drug effects
MH  - Metformin/*pharmacology
MH  - Mice
OTO - NOTNLM
OT  - Cerebral amyloid angiopathy
OT  - Insulin-degrading enzyme
OT  - Metformin
EDAT- 2021/07/27 06:00
MHDA- 2022/01/21 06:00
CRDT- 2021/07/26 20:12
PHST- 2021/01/25 00:00 [received]
PHST- 2021/06/23 00:00 [revised]
PHST- 2021/07/21 00:00 [accepted]
PHST- 2021/07/27 06:00 [pubmed]
PHST- 2022/01/21 06:00 [medline]
PHST- 2021/07/26 20:12 [entrez]
AID - S0304-3940(21)00514-0 [pii]
AID - 10.1016/j.neulet.2021.136136 [doi]
PST - ppublish
SO  - Neurosci Lett. 2021 Sep 25;762:136136. doi: 10.1016/j.neulet.2021.136136. Epub 
      2021 Jul 24.