APP in Autistic Children
APP in Autistic Children
Autism is characterized by restricted, repetitive behaviors and impairment in socialization and communication. Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor (BDNF) in neuropathologic and blood studies favor an anabolic state. We examined acetylcholinesterase, plasma neuronal proteins, secreted beta-amyloid precursor protein (APP), and amyloid-beta 40 and amyloid-beta 42 peptides in children with and without autism. 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. There was a trend for children with autism to show higher levels of secreted beta-amyloid precursor protein and nonamyloidogenic secreted beta-amyloid precursor protein and lower levels of amyloid-beta 40 compared with controls. This favors an increased a-secretase pathway in autism (anabolic), opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found.
Autism is associated with impairment in thinking, feeling, language, and the ability to relate to others. Autism is characterized by restricted, often repetitive behaviors and impairment in socialization and communication. The neuropathologic substrate underlying autism is unknown. Recent neuroimaging studies have determined that brain overgrowth occurs in young children (less than 6 years) with autism. The timing of such overgrowth is coincidental to the onset of symptoms. Accelerated brain growth has been associated with acquired macrocephaly, a clinical finding seen in many children with autism.
An anabolic state, representing brain overgrowth, has been suggested by an independent source of research: the study of brain-derived neurotrophic growth factor. This neurotrophin controls cholinergic neuronal development and maintenance. The brain neurotransmitter acetylcholine, its precursor choline, and the enzyme that breaks down acetylcholine, acetylcholinesterase, are substrates in the cholinergic system. Brain-derived neurotrophic growth factor was significantly elevated (three- to fivefold) in neuropathologic specimens of the cerebral cortex in adults with autism and in the blood of newborn autistic and other mentally retarded children. These results favor intrinsic cholinergic hypertrophy in individuals with autism.
The cholinergic system has been implicated in disorders associated with development (autism, Rett syndrome, and Down syndrome) and in old age (Alzheimer disease, Parkinson disease, and dementia with Lewy bodies). Although the cholinergic system has received less attention in autism than the monoaminergic (eg, serotonin, dopamine, and adrenaline) and neuropeptide (eg, opioid) systems, neuropathologic evidence has implicated choline in autism. Neuropathologic derangement was found in the basal forebrain cholinergic nuclei; extensive loss of α4, β2 nicotinic cholinergic receptors was found in the cerebral cortex of adults with autism. Although not yet established, there is speculation that the loss of this nicotinic receptor is linked to attentional abnormalities, pain perception, anxiety, and epilepsy, all clinical features of autism.
Alzheimer disease is characterized by progressive dementia in the elderly. Clinical similarities between autism and Alzheimer disease include disruption in language and social function. Neurochemically, Alzheimer disease is characterized by brain amyloid depositions, hyperphosphorylation of tau, loss of the synaptophysin protein, and cholinergic deficits. Recent evidence indicates that Alzheimer disease results from a series of steps in a pathogenic pathway that leads to amyloid formation and neurodegeneration in key areas of the brain involved in cognition and memory. The amyloid-beta peptide is the principal component of cerebral plaques. This is an insoluble 40- to 42-amino acid peptide.
The soluble amyloid-beta peptides can be detected in cell cultures, plasma, and cerebrospinal fluid. Amyloid-beta peptide is derived from a large type I integral membrane glycoprotein, beta-amyloid precursor protein with a large N-terminal extracellular domain, a single transmembrane domain, and a short cytoplasmic tail. A correlative memory deficit, amyloid-beta elevation, and amyloid plaques in transgenic mice have been shown.
Beta-amyloid precursor protein is processed by α-, β-, and γ-secretase enzymes. Beta-amyloid precursor protein is cleaved by β-secretase to produce a large, secreted derivative (secreted beta-amyloid precursor protein) and an amyloid beta-bearing C- terminal fragment. This amyloid beta C-terminal fragment is subsequently cleaved by γ-secretase to release amyloid-beta 1-40 or amyloid beta 1-42 fragments and the C-terminal fragment. Alternatively, at the cell surface, beta-amyloid precursor protein undergoes proteolysis by α-secretase that cleaves beta-amyloid precursor protein between Lys687 and Leu688, releasing a large, soluble ectodomain containing beta-amyloid precursor protein α. The a-secretase cleavage site lies within the amyloid-beta peptide associated with Alzheimer plaques. Therefore, an increase in asecretase activity has been found to be associated with a decrease in amyloid beta formation, and that is why it is otherwise known as the nonamyloidogenic pathway.
Down syndrome is characterized by microcephaly, hypotonia, and mental retardation. Up to 10% of individuals with Down syndrome develop autism, and many show progressive dementia with aging. The histopathologic changes of Alzheimer disease (senile plaques and neurofibrillary tangles) are commonly observed in persons with Down syndrome, especially beyond the third decade of life. Amyloid-beta peptides, which result from the processing of beta-amyloid precursor protein, appear in the brains of children with Down syndrome long before the deposition of cerebral plaques and can be detected in fetal brains. The selective binding of amyloid-beta peptides by the α7 nicotinic acetylcholine receptor has been shown to be cytotoxic in individuals with Down syndrome. Individuals with Down syndrome generally have elevated levels of beta-amyloid precursor protein but lower levels of amyloid-beta 40 and 42 until after the third decade of life.
To better understand the role of the same pathogenetic pathway involved in Alzheimer disease and Down syndrome in autism, we sought to establish the presence of serum acetylcholinesterase and plasma neuronal proteins (beta-amyloid precursor protein, amyloid-beta 40, amyloid-beta 42) in children with and without autism.
Autism is characterized by restricted, repetitive behaviors and impairment in socialization and communication. Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor (BDNF) in neuropathologic and blood studies favor an anabolic state. We examined acetylcholinesterase, plasma neuronal proteins, secreted beta-amyloid precursor protein (APP), and amyloid-beta 40 and amyloid-beta 42 peptides in children with and without autism. 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. There was a trend for children with autism to show higher levels of secreted beta-amyloid precursor protein and nonamyloidogenic secreted beta-amyloid precursor protein and lower levels of amyloid-beta 40 compared with controls. This favors an increased a-secretase pathway in autism (anabolic), opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found.
Autism is associated with impairment in thinking, feeling, language, and the ability to relate to others. Autism is characterized by restricted, often repetitive behaviors and impairment in socialization and communication. The neuropathologic substrate underlying autism is unknown. Recent neuroimaging studies have determined that brain overgrowth occurs in young children (less than 6 years) with autism. The timing of such overgrowth is coincidental to the onset of symptoms. Accelerated brain growth has been associated with acquired macrocephaly, a clinical finding seen in many children with autism.
An anabolic state, representing brain overgrowth, has been suggested by an independent source of research: the study of brain-derived neurotrophic growth factor. This neurotrophin controls cholinergic neuronal development and maintenance. The brain neurotransmitter acetylcholine, its precursor choline, and the enzyme that breaks down acetylcholine, acetylcholinesterase, are substrates in the cholinergic system. Brain-derived neurotrophic growth factor was significantly elevated (three- to fivefold) in neuropathologic specimens of the cerebral cortex in adults with autism and in the blood of newborn autistic and other mentally retarded children. These results favor intrinsic cholinergic hypertrophy in individuals with autism.
The cholinergic system has been implicated in disorders associated with development (autism, Rett syndrome, and Down syndrome) and in old age (Alzheimer disease, Parkinson disease, and dementia with Lewy bodies). Although the cholinergic system has received less attention in autism than the monoaminergic (eg, serotonin, dopamine, and adrenaline) and neuropeptide (eg, opioid) systems, neuropathologic evidence has implicated choline in autism. Neuropathologic derangement was found in the basal forebrain cholinergic nuclei; extensive loss of α4, β2 nicotinic cholinergic receptors was found in the cerebral cortex of adults with autism. Although not yet established, there is speculation that the loss of this nicotinic receptor is linked to attentional abnormalities, pain perception, anxiety, and epilepsy, all clinical features of autism.
Alzheimer disease is characterized by progressive dementia in the elderly. Clinical similarities between autism and Alzheimer disease include disruption in language and social function. Neurochemically, Alzheimer disease is characterized by brain amyloid depositions, hyperphosphorylation of tau, loss of the synaptophysin protein, and cholinergic deficits. Recent evidence indicates that Alzheimer disease results from a series of steps in a pathogenic pathway that leads to amyloid formation and neurodegeneration in key areas of the brain involved in cognition and memory. The amyloid-beta peptide is the principal component of cerebral plaques. This is an insoluble 40- to 42-amino acid peptide.
The soluble amyloid-beta peptides can be detected in cell cultures, plasma, and cerebrospinal fluid. Amyloid-beta peptide is derived from a large type I integral membrane glycoprotein, beta-amyloid precursor protein with a large N-terminal extracellular domain, a single transmembrane domain, and a short cytoplasmic tail. A correlative memory deficit, amyloid-beta elevation, and amyloid plaques in transgenic mice have been shown.
Beta-amyloid precursor protein is processed by α-, β-, and γ-secretase enzymes. Beta-amyloid precursor protein is cleaved by β-secretase to produce a large, secreted derivative (secreted beta-amyloid precursor protein) and an amyloid beta-bearing C- terminal fragment. This amyloid beta C-terminal fragment is subsequently cleaved by γ-secretase to release amyloid-beta 1-40 or amyloid beta 1-42 fragments and the C-terminal fragment. Alternatively, at the cell surface, beta-amyloid precursor protein undergoes proteolysis by α-secretase that cleaves beta-amyloid precursor protein between Lys687 and Leu688, releasing a large, soluble ectodomain containing beta-amyloid precursor protein α. The a-secretase cleavage site lies within the amyloid-beta peptide associated with Alzheimer plaques. Therefore, an increase in asecretase activity has been found to be associated with a decrease in amyloid beta formation, and that is why it is otherwise known as the nonamyloidogenic pathway.
Down syndrome is characterized by microcephaly, hypotonia, and mental retardation. Up to 10% of individuals with Down syndrome develop autism, and many show progressive dementia with aging. The histopathologic changes of Alzheimer disease (senile plaques and neurofibrillary tangles) are commonly observed in persons with Down syndrome, especially beyond the third decade of life. Amyloid-beta peptides, which result from the processing of beta-amyloid precursor protein, appear in the brains of children with Down syndrome long before the deposition of cerebral plaques and can be detected in fetal brains. The selective binding of amyloid-beta peptides by the α7 nicotinic acetylcholine receptor has been shown to be cytotoxic in individuals with Down syndrome. Individuals with Down syndrome generally have elevated levels of beta-amyloid precursor protein but lower levels of amyloid-beta 40 and 42 until after the third decade of life.
To better understand the role of the same pathogenetic pathway involved in Alzheimer disease and Down syndrome in autism, we sought to establish the presence of serum acetylcholinesterase and plasma neuronal proteins (beta-amyloid precursor protein, amyloid-beta 40, amyloid-beta 42) in children with and without autism.
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