title: Abnormal intracellular accumulation and extracellular Aβ deposition in idiopathic and Dup15q11.2-q13 autism spectrum disorders.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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 Aβ(17-40/42) 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 Aβ(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 Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques.
  
  
  CONCLUSIONS
  The higher prevalence of excessive Aβ 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 Aβ accumulation and diffuse plaque formation.
authors.affiliation: Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America. Jerzy.Wegiel@opwdd.ny.gov
authors.forename: Jerzy
authors.initials: J
authors.lastname: Wegiel
authors.forename: Janusz
authors.initials: J
authors.lastname: Frackowiak
authors.forename: Bozena
authors.initials: B
authors.lastname: Mazur-Kolecka
authors.forename: N Carolyn
authors.initials: NC
authors.lastname: Schanen
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Marian
authors.initials: M
authors.lastname: Sigman
authors.forename: W Ted
authors.initials: WT
authors.lastname: Brown
authors.forename: Izabela
authors.initials: I
authors.lastname: Kuchna
authors.forename: Jarek
authors.initials: J
authors.lastname: Wegiel
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Nowicki
authors.forename: Humi
authors.initials: H
authors.lastname: Imaki
authors.forename: Shuang Yong
authors.initials: SY
authors.lastname: Ma
authors.forename: Abha
authors.initials: A
authors.lastname: Chauhan
authors.forename: Ved
authors.initials: V
authors.lastname: Chauhan
authors.forename: David L
authors.initials: DL
authors.lastname: Miller
authors.forename: Pankaj D
authors.initials: PD
authors.lastname: Mehta
authors.forename: Michael
authors.initials: M
authors.lastname: Flory
authors.forename: Ira L
authors.initials: IL
authors.lastname: Cohen
authors.forename: Eric
authors.initials: E
authors.lastname: London
authors.forename: Barry
authors.initials: B
authors.lastname: Reisberg
authors.forename: Mony J
authors.initials: MJ
authors.lastname: de Leon
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
mesh_terms: D000293:Adolescent; D000328:Adult; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001321:Autistic Disorder / Q000378:metabolism*; D015153:Blotting, Western; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000378:metabolism*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides