PMID- 21347323
OWN - NLM
STAT- MEDLINE
DCOM- 20120402
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 2
DP  - 2011 Feb 10
TI  - The epsilon3 and epsilon4 alleles of human APOE differentially affect tau phosphorylation in 
      hyperinsulinemic and pioglitazone treated mice.
PG  - e16991
LID - 10.1371/journal.pone.0016991 [doi]
LID - e16991
AB  - BACKGROUND: Impaired insulin signalling is increasingly thought to contribute to 
      Alzheimer's disease (AD). The epsilon4 isoform of the APOE gene is the greatest genetic 
      risk factor for sporadic, late onset AD, and is also associated with risk for 
      type 2 diabetes mellitus (T2DM). Neuropathological studies reported the highest 
      number of AD lesions in brain tissue of epsilon4 diabetic patients. However other 
      studies assessing AD pathology amongst the diabetic population have produced 
      conflicting reports and have failed to show an increase in AD-related pathology 
      in diabetic brain. The thiazolidinediones (TZDs), peroxisome 
      proliferator-activated receptor gamma agonists, are peripheral insulin 
      sensitisers used to treat T2DM. The TZD, pioglitazone, improved memory and 
      cognitive functions in mild to moderate AD patients. Since it is not yet clear 
      how apoE isoforms influence the development of T2DM and its progression to AD, we 
      investigated amyloid beta and tau pathology in APOE knockout mice, carrying human 
      APOEepsilon3 or epsilon4 transgenes after diet-induced insulin resistance with and without 
      pioglitazone treatment. METHODS: Male APOE knockout, APOEepsilon3-transgenic and 
      APOEepsilon4-transgenic mice, together with background strain C57BL6 mice were kept on 
      a high fat diet (HFD) or low fat diet (LFD) for 32 weeks, or were all fed HFD for 
      32 weeks and during the final 3 weeks animals were treated with pioglitazone or 
      vehicle. RESULTS: All HFD animals developed hyperglycaemia with elevated plasma 
      insulin. Tau phosphorylation was reduced at 3 epitopes (Ser396, Ser202/Thr205 and 
      Thr231) in all HFD, compared to LFD, animals independent of APOE genotype. The 
      introduction of pioglitazone to HFD animals led to a significant reduction in tau 
      phosphorylation at the Ser202/Thr205 epitope in APOEepsilon3 animals only. We found no 
      changes in APP processing however the levels of soluble amyloid beta 40 was 
      reduced in APOE knockout animals treated with pioglitazone.
FAU - To, Alvina W M
AU  - To AW
AD  - King's College London, Institute of Psychiatry, London, United Kingdom.
FAU - Ribe, Elena M
AU  - Ribe EM
FAU - Chuang, Tsu Tshen
AU  - Chuang TT
FAU - Schroeder, Joern E
AU  - Schroeder JE
FAU - Lovestone, Simon
AU  - Lovestone S
LA  - eng
GR  - Biotechnology and Biological Sciences Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110210
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Thiazolidinediones)
RN  - 0 (tau Proteins)
RN  - X4OV71U42S (Pioglitazone)
SB  - IM
MH  - *Alleles
MH  - Amyloid beta-Peptides/chemistry/metabolism
MH  - Amyloid beta-Protein Precursor/metabolism
MH  - Animals
MH  - Apolipoproteins E/*genetics
MH  - Diabetes Mellitus, Type 2/etiology/genetics/metabolism
MH  - Diet, High-Fat/adverse effects
MH  - Genotype
MH  - Humans
MH  - Hyperinsulinism/etiology/*genetics/*metabolism
MH  - Hypoglycemic Agents/*pharmacology
MH  - Insulin Resistance/genetics
MH  - Male
MH  - Mice
MH  - Phosphorylation/drug effects/genetics
MH  - Pioglitazone
MH  - Solubility
MH  - Thiazolidinediones/*pharmacology
MH  - tau Proteins/chemistry/*metabolism
PMC - PMC3037394
COIS- Competing Interests: JE Scroeder and TT Chuang are employees of GlaxoSmithKline. 
      This does not alter the authors' adherence to PLoS ONE's policies on sharing data 
      and materials.
EDAT- 2011/02/25 06:00
MHDA- 2012/04/03 06:00
PMCR- 2011/02/10
CRDT- 2011/02/25 06:00
PHST- 2010/09/09 00:00 [received]
PHST- 2011/01/18 00:00 [accepted]
PHST- 2011/02/25 06:00 [entrez]
PHST- 2011/02/25 06:00 [pubmed]
PHST- 2012/04/03 06:00 [medline]
PHST- 2011/02/10 00:00 [pmc-release]
AID - PONE-D-10-02733 [pii]
AID - 10.1371/journal.pone.0016991 [doi]
PST - epublish
SO  - PLoS One. 2011 Feb 10;6(2):e16991. doi: 10.1371/journal.pone.0016991.