Abstract
BackgroundThe abnormal accumulation of amyloid-beta peptide is believed to cause malfunctioning of neurons in the Alzheimer's disease brain. Amyloid-beta exists in different assembly forms in the aging mammalian brain including monomers, oligomers, and aggregates, and in senile plaques, fibrils. Recent findings suggest that soluble amyloid-beta oligomers may represent the primary pathological species in Alzheimer's disease and the most toxic form that impairs synaptic and thus neuronal function. We previously reported the isolation of a novel amyloid-beta-degrading enzyme, acyl peptide hydrolase, a serine protease that degrades amyloid-beta, and is different in structure and activity from other amyloid-beta-degrading enzymes.ResultsHere we report the further characterization of acyl peptide hydrolase activity using mass spectrometry. Acyl peptide hydrolase cleaves the amyloid-beta peptide at amino acids 13, 14 and 19. In addition, by real-time PCR we found elevated acyl peptide hydrolase expression in brain areas rich in amyloid plaques suggesting that this enzyme's levels are responsive to increases in amyloid-beta levels. Lastly, tissue culture experiments using transfected CHO cells expressing APP751 bearing the V717F mutation indicate that acyl peptide hydrolase preferentially degrades dimeric and trimeric forms of amyloid-beta.ConclusionThese data suggest that acyl peptide hydrolase is involved in the degradation of oligomeric amyloid-beta, an activity that, if induced, might present a new tool for therapy aimed at reducing neurodegeneration in the Alzheimer's brain.
Highlights
The abnormal accumulation of amyloid-beta peptide is believed to cause malfunctioning of neurons in the Alzheimer's disease brain
Alzheimer's disease (AD) is a neurodegenerative disorder resulting from the pathological processing of Amyloid precursor protein (APP) that leads to the accumulation of amyloid-beta (Aβ) peptide, neuronal loss, synaptic dysfunction, inappropriate levels of neurotransmitters, and to irreversible and pro
In order to determine the exact cleavage sites in the Amyloid beta (Aβ) peptide, the acyl peptide hydrolase (APEH) enzyme that was purified from transfected cells was incubated with synthetic Aβ 1–40 for 5 hours
Summary
The abnormal accumulation of amyloid-beta peptide is believed to cause malfunctioning of neurons in the Alzheimer's disease brain. Amyloid-beta exists in different assembly forms in the aging mammalian brain including monomers, oligomers, and aggregates, and in senile plaques, fibrils. Recent findings suggest that soluble amyloid-beta oligomers may represent the primary pathological species in Alzheimer's disease and the most toxic form that impairs synaptic and neuronal function. Alzheimer's disease (AD) is a neurodegenerative disorder resulting from the pathological processing of APP that leads to the accumulation of amyloid-beta (Aβ) peptide, neuronal loss, synaptic dysfunction, inappropriate levels of neurotransmitters, and to irreversible and pro-. Altered metabolic balance between Aβ generation and Aβ degradation likely results in Aβ accumulation and in the change from Aβ monomers to the toxic forms of Aβ oligomers. To find ways to prevent Aβ oligomer accumulation in order to prevent neuronal toxicity and the cascade into neurodegeneration [13]
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