GFAP expression and social deficits in transgenic mice overexpressing human sAPPα

Antoinette R Bailey,Steven Barger,Tanya Murphy,Huayan Hou,Takashi Mori,Samantha Portis,Demian F Obregon,Saundra Stock,Jun Tan,Paul G Sanberg,Doug Shytle,Min Song

doi:10.1002/glia.22544

Abstract

Autistic individuals display impaired social interactions and language, and restricted, stereotyped behaviors. Elevated levels of secreted amyloid precursor protein-alpha (sAPPα), the product of α-secretase cleavage of APP, are found in the plasma of some individuals with autism. The sAPPα protein is neurotrophic and neuroprotective and recently showed a correlation to glial differentiation in human neural stem cells (NSCs) via the IL-6 pathway. Considering evidence of gliosis in postmortem autistic brains, we hypothesized that subsets of patients with autism would exhibit elevations in CNS sAPPα and mice generated to mimic this observation would display markers suggestive of gliosis and autism-like behavior. Elevations in sAPPα levels were observed in brains of autistic patients compared to controls. Transgenic mice engineered to overexpress human sAPPα (TgsAPPα mice) displayed hypoactivity, impaired sociability, increased brain glial fibrillary acidic protein (GFAP) expression, and altered Notch1 and IL-6 levels. NSCs isolated from TgsAPPα mice, and those derived from wild-type mice treated with sAPPα, displayed suppressed β-tubulin III and elevated GFAP expression. These results suggest that elevations in brain sAPPα levels are observed in subsets of individuals with autism and TgsAPPα mice display signs suggestive of gliosis and behavioral impairment.

Highlights

Autism is a heterogeneous neurodevelopmental disorder characterized by impaired communication, social interaction, and restricted, repetitive behaviors and interests (APA, 2000; Steyaert and De la Marche, 2008)
Results show that autistic patient brains contain a significantly increased level of secreted amyloid precursor protein-alpha (sAPPa) compared to the mean level found in the brains of normally developed controls (Fig. 1A)
These observations support our hypothesis that subsets of patients with autism exhibit elevations in CNS sAPPa and mice generated to mimic this observation display markers suggestive of gliosis and autism-like behavior

Summary

Introduction

Autism is a heterogeneous neurodevelopmental disorder characterized by impaired communication, social interaction, and restricted, repetitive behaviors and interests (APA, 2000; Steyaert and De la Marche, 2008). Patients with autism exhibit varied patterns of aberrant neuroanatomical and immunological features in addition to behavioral phenotypes (Bailey et al, 1998; Bauman and Kemper, 2005; Casanova et al, 2006; Amaral et al, 2008). Brain overgrowth followed by decelerated development is frequently observed in some autistic patients. This neuropathology is observed early in the developmental course and is thought to involve defects in the normal “pruning” of early neural network arbors. After proliferation and dendritic arbor formation, pruning and programmed cell death are highly regulated multifactorial processes dependent on ordered molecular and cellular interactions involving various players including neural stem cells (NSCs), astrocytes, and microglia.

Objectives

Methods

Results

Conclusion