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Mental Health - Neurological Disorders - Pediatrics and Child Health - Physiology

Abnormal Intracellular Accumulation and Extracellular Aß Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders
Published: Wednesday, May 02, 2012
Author: Jerzy Wegiel et al.

by Jerzy Wegiel, Janusz Frackowiak, Bozena Mazur-Kolecka, N. Carolyn Schanen, Edwin H. Cook, Marian Sigman, W. Ted Brown, Izabela Kuchna, Jarek Wegiel, Krzysztof Nowicki, Humi Imaki, Shuang Yong Ma, Abha Chauhan, Ved Chauhan, David L. Miller, Pankaj D. Mehta, Michael Flory, Ira L. Cohen, Eric London, Barry Reisberg, Mony J. de Leon, Thomas Wisniewski


It has been shown that amyloid ß (Aß), a product of proteolytic cleavage of the amyloid ß precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type–specific amount.

Methodology/Principal Findings

In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Aß load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Aß load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Aß was mainly N-terminally truncated. Increased intraneuronal accumulation of Aß17–40/42 in children and adults suggests a life-long enhancement of APP processing with a-secretase in autistic subjects. Aß accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced a-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Aß1–40/42 detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Aß and an extracellular deposition of full-length Aß in nonfibrillar plaques.


The higher prevalence of excessive Aß accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Aß accumulation and diffuse plaque formation.