Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain

Marzia Perluigi; Gilda Pupo; Antonella Tramutola; Chiara Cini; Raffaella Coccia; Eugenio Barone; Elizabeth Head; D. Allan Butterfield; Fabio Di Domenico

doi:10.1016/j.bbadis.2014.04.007

Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain

Marzia Perluigi, Gilda Pupo, Antonella Tramutola, Chiara Cini, Raffaella Coccia, Eugenio Barone, Elizabeth Head, D. Allan Butterfield, Fabio Di Domenico

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134 Scopus citations

Abstract

Down syndrome (DS) is the most frequent genetic cause of intellectual disability characterized by the presence of three copies of chromosome 21 (Chr21). Individuals with DS have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) after the age of 40. years. The aim of our study is to gain new insights in the molecular mechanisms impaired in DS subjects that eventually lead to the development of dementia. We evaluate the PI3K/Akt/mTOR axis in the frontal cortex from DS cases (under the age of 40. years) and DS with AD neuropathology compared with age-matched controls (Young and Old). The PI3K/Akt/mTOR axis may control several key pathways involved in AD that, if aberrantly regulated, affect amyloid beta (Aβ) deposition and tau phosphorylation. Our results show a hyperactivation of PI3K/Akt/mTOR axis in individuals with DS, with and without AD pathology, in comparison with respective controls. The PI3K/Akt/mTOR deregulation results in decreased autophagy, inhibition of IRS1 and GSK3β activity. Moreover, our data suggest that aberrant activation of the PI3K/Akt/mTOR axis acts in parallel to RCAN1 in phosphorylating tau, in DS and DS/AD. In conclusion, this study provides insights into the neuropathological mechanisms that may be engaged during the development of AD in DS. We suggest that deregulation of this signaling cascade is already evident in young DS cases and persist in the presence of AD pathology. The impairment of the PI3K/Akt/mTOR axis in DS population might represent a key-contributing factor to the neurodegenerative process that culminates in Alzheimer-like dementia.

Original language	English
Pages (from-to)	1144-1153
Number of pages	10
Journal	Biochimica et Biophysica Acta - Molecular Basis of Disease
Volume	1842
Issue number	7
DOIs	https://doi.org/10.1016/j.bbadis.2014.04.007
State	Published - Jul 2014

Bibliographical note

Funding Information:
All authors state that they have no conflicts of interest. This work was partially supported by PRIN2009 to C.C. and a NIH grant to D.A.B. [ A6-05119 ]. Brain tissue was acquired by EH under funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging Grant #NIH 1RO1HD064993-01 . Additional autopsy tissue was obtained from the UCI-ADRC (P50AG16573), from the UK ADC (P30AG28383) and from the NICHD Brain and Tissue Bank for Developmental Disorders of the University of Maryland, Baltimore, MD, contract HHSN275200900011C (N01HD90011). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords

Akt
Autophagy
Insulin signaling
PI3K
Trisomy 21
mTOR

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology

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10.1016/j.bbadis.2014.04.007

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title = "Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain",

abstract = "Down syndrome (DS) is the most frequent genetic cause of intellectual disability characterized by the presence of three copies of chromosome 21 (Chr21). Individuals with DS have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) after the age of 40. years. The aim of our study is to gain new insights in the molecular mechanisms impaired in DS subjects that eventually lead to the development of dementia. We evaluate the PI3K/Akt/mTOR axis in the frontal cortex from DS cases (under the age of 40. years) and DS with AD neuropathology compared with age-matched controls (Young and Old). The PI3K/Akt/mTOR axis may control several key pathways involved in AD that, if aberrantly regulated, affect amyloid beta (Aβ) deposition and tau phosphorylation. Our results show a hyperactivation of PI3K/Akt/mTOR axis in individuals with DS, with and without AD pathology, in comparison with respective controls. The PI3K/Akt/mTOR deregulation results in decreased autophagy, inhibition of IRS1 and GSK3β activity. Moreover, our data suggest that aberrant activation of the PI3K/Akt/mTOR axis acts in parallel to RCAN1 in phosphorylating tau, in DS and DS/AD. In conclusion, this study provides insights into the neuropathological mechanisms that may be engaged during the development of AD in DS. We suggest that deregulation of this signaling cascade is already evident in young DS cases and persist in the presence of AD pathology. The impairment of the PI3K/Akt/mTOR axis in DS population might represent a key-contributing factor to the neurodegenerative process that culminates in Alzheimer-like dementia.",

keywords = "Akt, Autophagy, Insulin signaling, PI3K, Trisomy 21, mTOR",

author = "Marzia Perluigi and Gilda Pupo and Antonella Tramutola and Chiara Cini and Raffaella Coccia and Eugenio Barone and Elizabeth Head and Butterfield, {D. Allan} and {Di Domenico}, Fabio",

note = "Funding Information: All authors state that they have no conflicts of interest. This work was partially supported by PRIN2009 to C.C. and a NIH grant to D.A.B. [ A6-05119 ]. Brain tissue was acquired by EH under funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging Grant #NIH 1RO1HD064993-01 . Additional autopsy tissue was obtained from the UCI-ADRC (P50AG16573), from the UK ADC (P30AG28383) and from the NICHD Brain and Tissue Bank for Developmental Disorders of the University of Maryland, Baltimore, MD, contract HHSN275200900011C (N01HD90011). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ",

year = "2014",

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doi = "10.1016/j.bbadis.2014.04.007",

language = "English",

volume = "1842",

pages = "1144--1153",

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AU - Perluigi, Marzia

AU - Pupo, Gilda

AU - Tramutola, Antonella

AU - Cini, Chiara

AU - Coccia, Raffaella

AU - Barone, Eugenio

AU - Head, Elizabeth

AU - Butterfield, D. Allan

AU - Di Domenico, Fabio

N1 - Funding Information: All authors state that they have no conflicts of interest. This work was partially supported by PRIN2009 to C.C. and a NIH grant to D.A.B. [ A6-05119 ]. Brain tissue was acquired by EH under funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging Grant #NIH 1RO1HD064993-01 . Additional autopsy tissue was obtained from the UCI-ADRC (P50AG16573), from the UK ADC (P30AG28383) and from the NICHD Brain and Tissue Bank for Developmental Disorders of the University of Maryland, Baltimore, MD, contract HHSN275200900011C (N01HD90011). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

PY - 2014/7

Y1 - 2014/7

N2 - Down syndrome (DS) is the most frequent genetic cause of intellectual disability characterized by the presence of three copies of chromosome 21 (Chr21). Individuals with DS have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) after the age of 40. years. The aim of our study is to gain new insights in the molecular mechanisms impaired in DS subjects that eventually lead to the development of dementia. We evaluate the PI3K/Akt/mTOR axis in the frontal cortex from DS cases (under the age of 40. years) and DS with AD neuropathology compared with age-matched controls (Young and Old). The PI3K/Akt/mTOR axis may control several key pathways involved in AD that, if aberrantly regulated, affect amyloid beta (Aβ) deposition and tau phosphorylation. Our results show a hyperactivation of PI3K/Akt/mTOR axis in individuals with DS, with and without AD pathology, in comparison with respective controls. The PI3K/Akt/mTOR deregulation results in decreased autophagy, inhibition of IRS1 and GSK3β activity. Moreover, our data suggest that aberrant activation of the PI3K/Akt/mTOR axis acts in parallel to RCAN1 in phosphorylating tau, in DS and DS/AD. In conclusion, this study provides insights into the neuropathological mechanisms that may be engaged during the development of AD in DS. We suggest that deregulation of this signaling cascade is already evident in young DS cases and persist in the presence of AD pathology. The impairment of the PI3K/Akt/mTOR axis in DS population might represent a key-contributing factor to the neurodegenerative process that culminates in Alzheimer-like dementia.

AB - Down syndrome (DS) is the most frequent genetic cause of intellectual disability characterized by the presence of three copies of chromosome 21 (Chr21). Individuals with DS have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) after the age of 40. years. The aim of our study is to gain new insights in the molecular mechanisms impaired in DS subjects that eventually lead to the development of dementia. We evaluate the PI3K/Akt/mTOR axis in the frontal cortex from DS cases (under the age of 40. years) and DS with AD neuropathology compared with age-matched controls (Young and Old). The PI3K/Akt/mTOR axis may control several key pathways involved in AD that, if aberrantly regulated, affect amyloid beta (Aβ) deposition and tau phosphorylation. Our results show a hyperactivation of PI3K/Akt/mTOR axis in individuals with DS, with and without AD pathology, in comparison with respective controls. The PI3K/Akt/mTOR deregulation results in decreased autophagy, inhibition of IRS1 and GSK3β activity. Moreover, our data suggest that aberrant activation of the PI3K/Akt/mTOR axis acts in parallel to RCAN1 in phosphorylating tau, in DS and DS/AD. In conclusion, this study provides insights into the neuropathological mechanisms that may be engaged during the development of AD in DS. We suggest that deregulation of this signaling cascade is already evident in young DS cases and persist in the presence of AD pathology. The impairment of the PI3K/Akt/mTOR axis in DS population might represent a key-contributing factor to the neurodegenerative process that culminates in Alzheimer-like dementia.

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KW - Autophagy

KW - Insulin signaling

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KW - Trisomy 21

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Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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