Dataset Information

Abnormal intracellular accumulation and extracellular A? deposition in idiopathic and Dup15q11.2-q13 autism spectrum disorders.

ABSTRACT:

Background

It has been shown that amyloid ß (A?), a product of proteolytic cleavage of the amyloid ? 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 A? 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 A? load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal A? was mainly N-terminally truncated. Increased intraneuronal accumulation of A?(17-40/42) in children and adults suggests a life-long enhancement of APP processing with ?-secretase in autistic subjects. A? accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced ?-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing A?(1-40/42) 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 A? and an extracellular deposition of full-length A? in nonfibrillar plaques.

Conclusions/significance

The higher prevalence of excessive A? 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 A? accumulation and diffuse plaque formation.

SUBMITTER: Wegiel J

PROVIDER: S-EPMC3342283 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Abnormal intracellular accumulation and extracellular Aβ deposition in idiopathic and Dup15q11.2-q13 autism spectrum disorders.

Wegiel Jerzy J Frackowiak Janusz J Mazur-Kolecka Bozena B Schanen N Carolyn NC Cook Edwin H EH Sigman Marian M Brown W Ted WT Kuchna Izabela I Wegiel Jarek J Nowicki Krzysztof K Imaki Humi H Ma Shuang Yong SY Chauhan Abha A Chauhan Ved V Miller David L DL Mehta Pankaj D PD Flory Michael M Cohen Ira L IL London Eric E Reisberg Barry B de Leon Mony J MJ Wisniewski Thomas T

PloS one 20120502 5

<h4>Background</h4>It has been shown that amyloid ß (Aβ), a product of proteolytic cleavage of the amyloid β precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type-specific amount.<h4>Methodology/principal findings</h4>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 s ...[more]

PMID: 22567102

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