Novel contribution of secreted amyloid-β precursor protein to white matter brain enlargement in autism spectrum disorder

Deborah Sokol, Bryan Maloney, Cara J. Westmark, Debomoy Lahiri

Research output: Contribution to journalReview article

1 Citation (Scopus)

Abstract

The most replicated neuroanatomical finding in autism is the tendency toward brain overgrowth, especially in younger children. Research shows that both gray and white matter are enlarged. Proposed mechanisms underlying brain enlargement include abnormal inflammatory and neurotrophic signals that lead to excessive, aberrant dendritic connectivity via disrupted pruning and cell adhesion, and enlargement of white matter due to excessive gliogenesis and increased myelination. Amyloid-β protein precursor (βAPP) and its metabolites, more commonly associated with Alzheimer's disease (AD), are also dysregulated in autism plasma and brain tissue samples. This review highlights findings that demonstrate how one βAPP metabolite, secreted APPα, and the ADAM family α-secretases, may lead to increased brain matter, with emphasis on increased white matter as seen in autism. sAPPα and the ADAM family α-secretases contribute to the anabolic, non-amyloidogenic pathway, which is in contrast to the amyloid (catabolic) pathway known to contribute to Alzheimer disease. The non-amyloidogenic pathway could produce brain enlargement via genetic mechanisms affecting mRNA translation and polygenic factors that converge on molecular pathways (mitogen-activated protein kinase/MAPK and mechanistic target of rapamycin/mTOR), promoting neuroinflammation. A novel mechanism linking the non-amyloidogenic pathway to white matter enlargement is proposed: α-secretase and/or sAPPα, activated by ERK receptor signaling activates P13K/AKt/mTOR and then Rho GTPases favoring myelination via oligodendrocyte progenitor cell (OPC) activation of cofilin. Applying known pathways in AD to autism should allow further understanding and provide options for new drug targets.

Original languageEnglish (US)
Article number165
JournalFrontiers in Psychiatry
Volume10
Issue numberAPR
DOIs
StatePublished - Jan 1 2019

Fingerprint

Amyloid beta-Protein Precursor
Autistic Disorder
Amyloid Precursor Protein Secretases
Brain
Alzheimer Disease
Cell Enlargement
Actin Depolymerizing Factors
rho GTP-Binding Proteins
Oligodendroglia
Protein Biosynthesis
Sirolimus
Mitogen-Activated Protein Kinases
Amyloid
Cell Adhesion
Stem Cells
White Matter
Autism Spectrum Disorder
Research
Pharmaceutical Preparations

Keywords

  • Amyloid
  • Anabolic
  • Biomarker
  • Brain overgrowth
  • Comorbidity
  • Metabolites
  • Neurodevelopmental
  • Secretase

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Novel contribution of secreted amyloid-β precursor protein to white matter brain enlargement in autism spectrum disorder. / Sokol, Deborah; Maloney, Bryan; Westmark, Cara J.; Lahiri, Debomoy.

In: Frontiers in Psychiatry, Vol. 10, No. APR, 165, 01.01.2019.

Research output: Contribution to journalReview article

@article{4128fb8cab164fec8718c8b62762a2d5,
title = "Novel contribution of secreted amyloid-β precursor protein to white matter brain enlargement in autism spectrum disorder",
abstract = "The most replicated neuroanatomical finding in autism is the tendency toward brain overgrowth, especially in younger children. Research shows that both gray and white matter are enlarged. Proposed mechanisms underlying brain enlargement include abnormal inflammatory and neurotrophic signals that lead to excessive, aberrant dendritic connectivity via disrupted pruning and cell adhesion, and enlargement of white matter due to excessive gliogenesis and increased myelination. Amyloid-β protein precursor (βAPP) and its metabolites, more commonly associated with Alzheimer's disease (AD), are also dysregulated in autism plasma and brain tissue samples. This review highlights findings that demonstrate how one βAPP metabolite, secreted APPα, and the ADAM family α-secretases, may lead to increased brain matter, with emphasis on increased white matter as seen in autism. sAPPα and the ADAM family α-secretases contribute to the anabolic, non-amyloidogenic pathway, which is in contrast to the amyloid (catabolic) pathway known to contribute to Alzheimer disease. The non-amyloidogenic pathway could produce brain enlargement via genetic mechanisms affecting mRNA translation and polygenic factors that converge on molecular pathways (mitogen-activated protein kinase/MAPK and mechanistic target of rapamycin/mTOR), promoting neuroinflammation. A novel mechanism linking the non-amyloidogenic pathway to white matter enlargement is proposed: α-secretase and/or sAPPα, activated by ERK receptor signaling activates P13K/AKt/mTOR and then Rho GTPases favoring myelination via oligodendrocyte progenitor cell (OPC) activation of cofilin. Applying known pathways in AD to autism should allow further understanding and provide options for new drug targets.",
keywords = "Amyloid, Anabolic, Biomarker, Brain overgrowth, Comorbidity, Metabolites, Neurodevelopmental, Secretase",
author = "Deborah Sokol and Bryan Maloney and Westmark, {Cara J.} and Debomoy Lahiri",
year = "2019",
month = "1",
day = "1",
doi = "10.3389/fpsyt.2019.00165",
language = "English (US)",
volume = "10",
journal = "Frontiers in Psychiatry",
issn = "1664-0640",
publisher = "Frontiers Research Foundation",
number = "APR",

}

TY - JOUR

T1 - Novel contribution of secreted amyloid-β precursor protein to white matter brain enlargement in autism spectrum disorder

AU - Sokol, Deborah

AU - Maloney, Bryan

AU - Westmark, Cara J.

AU - Lahiri, Debomoy

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The most replicated neuroanatomical finding in autism is the tendency toward brain overgrowth, especially in younger children. Research shows that both gray and white matter are enlarged. Proposed mechanisms underlying brain enlargement include abnormal inflammatory and neurotrophic signals that lead to excessive, aberrant dendritic connectivity via disrupted pruning and cell adhesion, and enlargement of white matter due to excessive gliogenesis and increased myelination. Amyloid-β protein precursor (βAPP) and its metabolites, more commonly associated with Alzheimer's disease (AD), are also dysregulated in autism plasma and brain tissue samples. This review highlights findings that demonstrate how one βAPP metabolite, secreted APPα, and the ADAM family α-secretases, may lead to increased brain matter, with emphasis on increased white matter as seen in autism. sAPPα and the ADAM family α-secretases contribute to the anabolic, non-amyloidogenic pathway, which is in contrast to the amyloid (catabolic) pathway known to contribute to Alzheimer disease. The non-amyloidogenic pathway could produce brain enlargement via genetic mechanisms affecting mRNA translation and polygenic factors that converge on molecular pathways (mitogen-activated protein kinase/MAPK and mechanistic target of rapamycin/mTOR), promoting neuroinflammation. A novel mechanism linking the non-amyloidogenic pathway to white matter enlargement is proposed: α-secretase and/or sAPPα, activated by ERK receptor signaling activates P13K/AKt/mTOR and then Rho GTPases favoring myelination via oligodendrocyte progenitor cell (OPC) activation of cofilin. Applying known pathways in AD to autism should allow further understanding and provide options for new drug targets.

AB - The most replicated neuroanatomical finding in autism is the tendency toward brain overgrowth, especially in younger children. Research shows that both gray and white matter are enlarged. Proposed mechanisms underlying brain enlargement include abnormal inflammatory and neurotrophic signals that lead to excessive, aberrant dendritic connectivity via disrupted pruning and cell adhesion, and enlargement of white matter due to excessive gliogenesis and increased myelination. Amyloid-β protein precursor (βAPP) and its metabolites, more commonly associated with Alzheimer's disease (AD), are also dysregulated in autism plasma and brain tissue samples. This review highlights findings that demonstrate how one βAPP metabolite, secreted APPα, and the ADAM family α-secretases, may lead to increased brain matter, with emphasis on increased white matter as seen in autism. sAPPα and the ADAM family α-secretases contribute to the anabolic, non-amyloidogenic pathway, which is in contrast to the amyloid (catabolic) pathway known to contribute to Alzheimer disease. The non-amyloidogenic pathway could produce brain enlargement via genetic mechanisms affecting mRNA translation and polygenic factors that converge on molecular pathways (mitogen-activated protein kinase/MAPK and mechanistic target of rapamycin/mTOR), promoting neuroinflammation. A novel mechanism linking the non-amyloidogenic pathway to white matter enlargement is proposed: α-secretase and/or sAPPα, activated by ERK receptor signaling activates P13K/AKt/mTOR and then Rho GTPases favoring myelination via oligodendrocyte progenitor cell (OPC) activation of cofilin. Applying known pathways in AD to autism should allow further understanding and provide options for new drug targets.

KW - Amyloid

KW - Anabolic

KW - Biomarker

KW - Brain overgrowth

KW - Comorbidity

KW - Metabolites

KW - Neurodevelopmental

KW - Secretase

UR - http://www.scopus.com/inward/record.url?scp=85067964827&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067964827&partnerID=8YFLogxK

U2 - 10.3389/fpsyt.2019.00165

DO - 10.3389/fpsyt.2019.00165

M3 - Review article

AN - SCOPUS:85067964827

VL - 10

JO - Frontiers in Psychiatry

JF - Frontiers in Psychiatry

SN - 1664-0640

IS - APR

M1 - 165

ER -