Abnormal Intracellular Accumulation and Extracellular Aβ Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders
Jerzy Wegiel, 1 , * Janusz Frackowiak, 1 Bozena Mazur-Kolecka, 1N. Carolyn Schanen, 2 Edwin H. Cook, Jr., 3 Marian Sigman, 4 W. Ted Brown, 5Izabela Kuchna, 1 Jarek Wegiel, 1 Krzysztof Nowicki, 1 Humi Imaki, 1Shuang Yong Ma, 1 Abha Chauhan, 6 Ved Chauhan, 6 David L. Miller, 7Pankaj D. Mehta, 1 Michael Flory, 8 Ira L. Cohen, 8 Eric London, 8 Barry Reisberg,9 Mony J. de Leon, 9 and Thomas Wisniewski 1 , 9
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.
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 Aβ 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 Aβ load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Aβ was mainly N-terminally truncated. Increased intraneuronal accumulation of Aβ17–40/42 in children and adults suggests a life-long enhancement of APP processing with α-secretase in autistic subjects. Aβ accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced α-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Aβ1–40/42 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 Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques.