PMID- 25645581
OWN - NLM
STAT- MEDLINE
DCOM- 20150624
LR  - 20211203
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Linking)
VI  - 133
IP  - 5
DP  - 2015 Jun
TI  - Alteration of mTOR signaling occurs early in the progression of Alzheimer disease 
      (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild 
      cognitive impairment and late-stage AD.
PG  - 739-49
LID - 10.1111/jnc.13037 [doi]
AB  - The clinical symptoms of Alzheimer disease (AD) include a gradual memory loss and 
      subsequent dementia, and neuropathological deposition of senile plaques and 
      neurofibrillary tangles. At the molecular level, AD subjects present overt 
      amyloid beta (Abeta) production and tau hyperphosphorylation. Abeta species have been 
      proposed to overactivate the phosphoinositide3-kinase (PI3K)/Akt/mammalian target 
      of rapamycin (mTOR) axis, which plays a central role in proteostasis. The current 
      study investigated the status of the PI3K/Akt/mTOR pathway in post-mortem tissue 
      from the inferior parietal lobule (IPL) at three different stages of AD: late AD, 
      amnestic mild cognitive impairment (MCI) and pre-clinical AD (PCAD). Our findings 
      suggest that the alteration of mTOR signaling and autophagy occurs at early 
      stages of AD. We found a significant increase in Abeta (1-42) levels, associated 
      with reduction in autophagy (Beclin-1 and LC-3) observed in PCAD, MCI, and AD 
      subjects. Related to the autophagy impairment, we found a hyperactivation of 
      PI3K/Akt/mTOR pathway in IPL of MCI and AD subjects, but not in PCAD, along with 
      a significant decrease in phosphatase and tensin homolog. An increase in two mTOR 
      downstream targets, p70S6K and 4EBP1, occurred in AD and MCI subjects. Both AD 
      and MCI subjects showed increased, insulin receptor substrate 1, a candidate 
      biomarker of brain insulin resistance, and GSK-3beta, a kinase targeting tau 
      phosphorylation. Nevertheless, tau phosphorylation was increased in the clinical 
      groups. The results hint at a link between Abeta and the PI3K/Akt/mTOR axis and 
      provide further insights into the relationship between AD pathology and insulin 
      resistance. In addition, we speculate that the alteration of mTOR signaling in 
      the IPL of AD and MCI subjects, but not in PCAD, is due to the lack of 
      substantial increase in oxidative stress. The figure represents the three 
      different stages of Alzheimer Disease: Preclinical Alzheimer Disease (PCAD), Mild 
      cognitive impairment (MCI) and late stage of Alzheimer Disease. The progression 
      of the disease is associated with a reduction in autophagy (Beclin-1 and LC-3) 
      observed in Inferior parietal lobe of PCAD, MCI, and AD subjects (light red). 
      Related to the autophagy impairment, the graph shows the impairment of 
      PI3K/Akt/mTOR in MCI and AD subjects (dark red).
CI  - (c) 2015 International Society for Neurochemistry.
FAU - Tramutola, Antonella
AU  - Tramutola A
AD  - Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy.
FAU - Triplett, Judy C
AU  - Triplett JC
FAU - Di Domenico, Fabio
AU  - Di Domenico F
FAU - Niedowicz, Dana M
AU  - Niedowicz DM
FAU - Murphy, Michael P
AU  - Murphy MP
FAU - Coccia, Raffaella
AU  - Coccia R
FAU - Perluigi, Marzia
AU  - Perluigi M
FAU - Butterfield, D Allan
AU  - Butterfield DA
LA  - eng
PT  - Journal Article
DEP - 20150226
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (tau Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Aged, 80 and over
MH  - Alzheimer Disease/*physiopathology/psychology
MH  - Amnesia/*physiopathology/psychology
MH  - Amyloid beta-Peptides/analysis/metabolism
MH  - Autophagy
MH  - *Brain Chemistry
MH  - Cognitive Dysfunction/*physiopathology/psychology
MH  - Disease Progression
MH  - Female
MH  - Humans
MH  - Insulin Resistance
MH  - Male
MH  - Oncogene Protein v-akt/physiology
MH  - Phosphatidylinositol 3-Kinases/physiology
MH  - Signal Transduction/physiology
MH  - TOR Serine-Threonine Kinases/*physiology
MH  - tau Proteins/metabolism
OTO - NOTNLM
OT  - Alzheimer disease progression
OT  - Preclinical Alzheimer disease
OT  - amnestic Mild Cognitive Impairment (MCI)
OT  - mTOR signaling, autophagy
EDAT- 2015/02/04 06:00
MHDA- 2015/06/25 06:00
CRDT- 2015/02/04 06:00
PHST- 2014/10/20 00:00 [received]
PHST- 2014/12/19 00:00 [revised]
PHST- 2015/01/12 00:00 [accepted]
PHST- 2015/02/04 06:00 [entrez]
PHST- 2015/02/04 06:00 [pubmed]
PHST- 2015/06/25 06:00 [medline]
AID - 10.1111/jnc.13037 [doi]
PST - ppublish
SO  - J Neurochem. 2015 Jun;133(5):739-49. doi: 10.1111/jnc.13037. Epub 2015 Feb 26.