Levels of Alzheimer Beta-Amyloid Precursor Protein (APP) in Children With Severely Autistic Behavior and Aggression

Deborah K. Sokol PhD, MD; Demao Chen PhD; Martin R.Farlow MD; David W. Dunn MD; Bryan Maloney BA; Jennifer A. Zimmer MD; Debomoy K. Lahiri PhD

Disclosures

J Child Neurol. 2006;21(6):444-449. 

In This Article

Discussion

Our aim was to investigate the neurobiologic mechanism involved in autism based on the hypothesis of the participation of cholinergic and amyloid pathways in early brain development or its aberration. We measured levels of serum acetylcholinesterase and plasma neuronal proteins (beta-amyloid precursor protein, amyloid-beta 40, amyloid-beta 42) in children with and without autism. We noted several interesting trends, and, in particular, our results suggest that both secreted beta-amyloid precursor protein and secreted beta-amyloid precursor protein a levels were increased in the group of children with autism with aggression compared with controls. Levels of amyloid-beta 40 were decreased in children with autism (no significance). Despite the major limitation of a small sample size used in this study, a few significant findings were seen. We found a complicated relationship between the severity of autism, age, acetylcholinesterase, and the plasma protein markers. Children with severe autism and aggression expressed secreted beta-amyloid precursor protein at two or more times the levels of children without autism and up to four times more than children with mild autism. Overall, there was a trend toward higher levels of total secreted beta-amyloid precursor protein and secreted beta-amyloid precursor protein a within the children with autism, with a concomitant decrease in amyloid-beta 40. Could the a-secretase pathway be increased in autism, favoring an anabolic state, consistent with brain overgrowth? Inspection of the data shows that the individuals with fragile X syndrome had the highest levels of secreted beta-amyloid precursor protein. Fragile X syndrome but not autism, per se, might then uniquely contribute to elevation in secreted beta-amyloid precursor protein and deserves isolated study.

One of the three children with autism and aggression also showing high levels of beta-amyloid precursor protein had the sickle cell trait. Sickle cell disease results from a point mutation gene that transforms hemoglobin A to hemoglobin S, causing sickling of blood cells and vaso-occlusion. Homozygous hemoglobin S results in the disease; heterozygous hemoglobin S results in the trait, which can be clinically silent. Inflammation is involved in sickle cell disease because patients with this disease have increased levels of serum C-reactive protein, cytokines, interleukin-6, and transcription factor nuclear factor κB.[18] Such an inflammatory response is seen in Alzheimer disease, and we speculate that interleukin-6 and nuclear factor κB could increase transcription of the beta-amyloid precursor protein gene, resulting in more production of this precursor protein. Similarly, autism has been linked to an inflammatory response, favoring production of beta-amyloid precursor protein.[19]

The trend toward decreased amyloid-beta 40 is consistent with the lack of cerebral plaques found on neuropathologic examination of the brains of individuals with autism.[7] Although the elevation of secreted beta-amyloid precursor protein is consistent with that seen in Down syndrome, the trend toward decreased amyloid beta 40 is different because elevated amyloid beta 40 is seen in individuals with Down syndrome.[14] Because individuals with Down syndrome are microcephalic and those with autism can be macrocephalic, it remains to be seen if amyloid beta 40 causes cytotoxic changes contributing to microcephaly in Down syndrome. This is only speculation because the results of the present study must be interpreted with caution owing to its low power.

The relatively robust findings in this study were the negative correlations between beta-amyloid precursor protein and age and between beta-amyloid precursor protein and acetylcholinesterase and the positive correlation between age and acetylcholinesterase, seen for the entire sample and for subsamples of children without seizures. A negative correlation of age and beta-amyloid precursor protein suggests that beta-amyloid precursor protein is reduced as one ages, an association observed by Zhang.[20] The positive correlation of acetylcholinesterase and age favors decreased acetylcholine as one ages, a finding supported by developmental studies of cholinergic brain levels as measured by proton magnetic resonance spectroscopy.[21] Further studies of acetylcholinesterase and plasma protein markers in larger samples of children are needed.

The present research, although done with a small number of subjects, has great potential for understanding the neurobiologic pathway in autism and the role of beta-amyloid precursor protein in its etiology. Our present results give credibility to the "anabolic theory" of autism, which could mostly be orchestrated by high levels of secreted beta-amyloid precursor protein a and other growth factors for the following reasons. First, alternative processing of beta-amyloid precursor protein by a-secretase, which results in the formation of secreted beta-amyloid precursor protein a, precludes the production of potentially toxic amyloid-beta proteins, and this is consistent with the lack of amyloid beta plaques observed in autism. Second, the C-terminal truncated full-length beta-amyloid precursor protein (secreted beta-amyloid precursor protein α) has been shown to provide neuroprotection,[22] and proteolytic products of beta-amyloid precursor protein are believed to influence the cholinergic system.[18] The important function of beta-amyloid precursor protein is evident from knockout studies, which indicated that double beta-amyloid precursor protein is lethal to mice. Third, growth factors, including neurotrophic growth factor and brain-derived neurotrophic growth factor, have been shown to increase beta-amyloid precursor protein activity.[22] This leads to the following question: Does severe autism with aggression represent abnormal activity with neurotic outgrowth and the reversal of age-related neurodegeneration? The beta-amyloid precursor protein gene is located on chromosome 21, the same chromosome that is duplicated in trisomy 21 (Down syndrome). In general, individuals with Alzheimer disease have reduced levels of secreted beta-amyloid precursor protein a and elevated levels of amyloid-beta 40 and amyloid-beta 42 (just the opposite scenario of autism). Finally, it is interesting to mention that at least one of the amyloid precursor protein binding protein (APBA-2) genes localizes to chromosome 15, and this gene recently has been reported with late-onset Alzheimer disease.[23] Notably, the amyloid precursor protein binding protein 2 gene was previously mapped to the distal portion of the interval commonly deleted in Prader-Willi and Angelman syndromes and duplicated in cases of autism.[24]

Taken together, our present observation of increased levels of secreted beta-amyloid precursor protein in a small group of children with severe autism with aggression is significant, with implications of future drug target development strategy for autism. The role of beta-amyloid precursor protein, beta-amyloid precursor protein binding proteins and their interactions with brain-derived neurotrophic growth factor warrant further investigation both at the clinical level, within a larger patient population, and at the mechanistic level by determining the relationship of beta-amyloid precursor protein with other relevant protein markers.


CLICK HERE for subscription information about this journal.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....