PMID- 23470275
OWN - NLM
STAT- MEDLINE
DCOM- 20140220
LR  - 20220330
IS  - 1873-6815 (Electronic)
IS  - 0531-5565 (Linking)
VI  - 48
IP  - 7
DP  - 2013 Jul
TI  - PI3-kinase/Akt/mTOR signaling: impaired on/off switches in aging, cognitive 
      decline and Alzheimer's disease.
PG  - 647-53
LID - S0531-5565(13)00065-X [pii]
LID - 10.1016/j.exger.2013.02.025 [doi]
AB  - The normal on and off switching of the PI3-K (phosphoinositide 3-kinase)/Akt 
      pathway, particularly by its major activators insulin and IGF-1 (insulin-like 
      growth factor-1), is a powerful integrator of physiological responses rudimentary 
      to successful aging. This is highlighted by extensive studies showing that 
      reducing, but not obliterating, activation of the PI3-K/Akt/mTOR signal, at 
      several levels, can extend healthy lifespan in organisms from yeast to mammals. 
      Moreover, aberrant control of the PI3-K/Akt axis is emerging to be a primary 
      causative node in all major diseases of aging: cancer, type 2 diabetes mellitus 
      (T2DM), heart disease and neurodegeneration. Aging is the major risk factor for 
      AD, the most common dementia disorder. The integrated coordination of neuronal 
      responses through the PI3-K/Akt pathway has significant functional impact on key 
      events that go awry in Alzheimer's disease (AD), including: synaptic plasticity, 
      neuronal polarity, neurotransmission, proteostasis, use-dependent translation, 
      metabolic control and stress responses including DNA repair. Investigation of the 
      status of the PI3-K/Akt system in brains of individuals who have had AD shows 
      aberrant and sustained activation of neuronal PI3-K/Akt/mTOR signaling to be an 
      early feature of the disease. This is mechanistically linked to progressive 
      desensitization of normal brain insulin and IGF-1 responses, aberrant 
      proteostasis of Abeta and tau, synaptic loss and cognitive decline in the disease. 
      Notably, concomitantly with feedback inhibition of insulin and IGF-1 responses, 
      increased activation of the neuronal PI3-K/Akt/mTOR axis is a major candidate 
      effector system for transmission of pathophysiological signals from Abeta to tau in 
      the context of defects in synaptic transmission that lead to cognitive decline. 
      Therapeutic approaches targeted at normalizing signaling through either the 
      neuronal PI3-kinase/Akt/mTOR pathway or its activation by insulin and IGF-1 have 
      been shown to be protective against the development of AD pathology and cognitive 
      decline in animal models of AD and some of these therapies are entering clinical 
      trials in patients with the disease.
CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
FAU - O' Neill, Cora
AU  - O' Neill C
AD  - Department of Biochemistry, BioSciences Institute, University College Cork, 
      Ireland. c.oneill@ucc.ie
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20130305
PL  - England
TA  - Exp Gerontol
JT  - Experimental gerontology
JID - 0047061
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Age Factors
MH  - Aging/*metabolism/psychology
MH  - Alzheimer Disease/drug therapy/*enzymology/physiopathology/psychology
MH  - Animals
MH  - Brain/drug effects/*enzymology/physiopathology
MH  - *Cognition/drug effects
MH  - Cognition Disorders/drug therapy/*enzymology/physiopathology/psychology
MH  - Humans
MH  - Molecular Targeted Therapy
MH  - Phosphatidylinositol 3-Kinase/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/therapeutic use
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/*metabolism
MH  - *Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
EDAT- 2013/03/09 06:00
MHDA- 2014/02/22 06:00
CRDT- 2013/03/09 06:00
PHST- 2012/10/22 00:00 [received]
PHST- 2013/02/07 00:00 [revised]
PHST- 2013/02/15 00:00 [accepted]
PHST- 2013/03/09 06:00 [entrez]
PHST- 2013/03/09 06:00 [pubmed]
PHST- 2014/02/22 06:00 [medline]
AID - S0531-5565(13)00065-X [pii]
AID - 10.1016/j.exger.2013.02.025 [doi]
PST - ppublish
SO  - Exp Gerontol. 2013 Jul;48(7):647-53. doi: 10.1016/j.exger.2013.02.025. Epub 2013 
      Mar 5.