Amyloid beta-protein^sub 1-40^ (AP40) is a low molecular weight peptide produced throughout life during normal cell metabolism and neurodegenerative diseases. Owing to its neurotrophic and neurotoxic effects, the present study was conducted to evaluate serum levels of AP40 in healthy subjects, autistic children and Alzheimer's disease patients. Serum AP40 was measured by enzyme-linked immunosorbent assay (ELISA). AP40 was significantly higher in normal children compared to normal older controls, in normal children compared to autistic children, and in autistic children compared to Alzheimer's patients (p value was less than 0.05 for all groups). This finding suggests an age-related decline of serum AP40 in normal aging, as well as in autism and Alzheimer's disease. This decline may result from abnormal processing of amyloid beta-protein precursor (APP) during normal aging and age-related diseases such as autism in children and Alzheimer's disease in elderly. Possible explanations for this decline may include age-related increased interactions of AP40 with cytoskeletal proteins for brain tissue deposition, increased serine proteases for APP metabolism or hyperimmune reaction (antibodies to AP40) for removal of circulating AP40. To conclude, the AP40 metabolism declines with normal aging and in addition to its role in Alzheimer's disease this protein might also be a contributing factor in autism.
Key Words: Autism; Amyloid-beta protein, Alzheimer's disease; Aging, Neuropathology
(ProQuest: ... denotes non-US-ASCII text omitted.)
Accumulation of AP40 occurs in the brain during normal aging but its amount is increased in the brain of patients with Alzheimer's disease (1). In addition to brain, AP40 has been localized outside the brain in skin fibroblasts and biological fluids, including the blood serum. AP40 is well known to exhibit both neurotrophic and neurotoxic effects (2-4), including neurogenic action on neural stem cells (5). Considering these properties, we hypothesized that AP40 might play a pathogenic role in autism.
Autism is an early-onset disorder of the developing central nervous system (CNS), manifesting both neurological and behavioral impairments. The disorder causes severe deficits of higher mental functions such as social interaction, language, cognition, communication, and imagination. Autism is the fastest-growing developmental disability today. The disorder affects millions of people worldwide, but very little is known about the etiology and pathogenesis of the disorder. Current theories include genetic factors, immune factors, environmental factors and yet other unidentified factors. The evidence is rapidly accumulating to support "autoimmune hypothesis" in autism (6-10). Autoimmunity in autistic children is shown by several autoimmune factors: brain-specific autoantibodies, impaired lymphocyte functions, abnormal cytokine regulation, viral association, linkage of certain immunogenetic factors, and response to immune modulation therapy (6-10).
The present study describes results of laboratory analysis of serum AP40, which was found to decline during normal aging, autistic children and Alzheimer's patients. Preliminary findings of this study were presented elsewhere (11).
Human Subjects and Methods
The study included 53 normal children (age 3-13 yrs), 9 normal adults (age 25-40 yrs), 9 normal aged controls (age 50-80 yrs), 53 autistic children (age 4-12 yrs) and 21 Alzheimer's disease patients (age 60-82 yrs). The clinical diagnosis of autism was made essentially according to the standard DSM-IV criteria of the American Association of Psychiatrists, Washington, DC. Neurologists made the clinical diagnosis of Alzheimer's disease (AD) according to the NINCDS-ADRDA criteria, which also included a 'Mini-Mental State' examination and a two-year downward course of the disease progression. The IRB of Utah State University and the University of Michigan reviewed and approved our research protocol involving the use of human blood samples (6-8). …