RESUMO
Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alpha-secretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Abeta) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Abeta degradation and clearance.
Assuntos
Envelhecimento/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/enzimologia , Síndrome de Down/enzimologia , Adolescente , Adulto , Idoso , Envelhecimento/patologia , Biomarcadores/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Progressão da Doença , Síndrome de Down/patologia , Síndrome de Down/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Placa Amiloide/enzimologia , Placa Amiloide/patologia , Valores de Referência , Regulação para Cima/fisiologiaRESUMO
The current study describes both Abeta and tau abnormalities that accumulate in the brains of aged (16-21 years), but not young (<4 years) clinically characterized cats. Diffuse plaques that were morphologically different from what is typically observed in the human brain could be detected with 4G8 (Abeta17-24) or an Abeta1-42-specific antibody but not with N-terminal Abeta or an Abeta1-40-specific antibody. SELDI-TOF mass spectrometry experiments indicated that cat brain Abeta consisted almost entirely of Abeta1-42. Markers of tau hyperphosphorylation (AT8 and PHF-1) labeled a subset of neurons in two aged animals. In the hilus of the hippocampus, a subset of AT8 positive neurons showed a sprouting morphology similar to that observed in human brain. Western blot analysis with antibodies against hyperphosphorylated tau indicated that tau is hyperphosphorylated in the aged cat and contains many of the same epitopes found in Alzheimer's disease (AD) brain. Thus, the aged cat brain develops AD-related lesions with important morphological and biochemical differences compared to human brain.