Abnormal Intracellular Accumulation and Extracellular Aβ Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders

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