TY - JOUR
T1 - Age- and region-dependent alterations in Aβ-degrading enzymes
T2 - Implications for Aβ-induced disorders
AU - Caccamo, Antonella
AU - Oddo, Salvatore
AU - Sugarman, Michael C.
AU - Akbari, Yama
AU - LaFerla, Frank M.
N1 - Funding Information:
We thank Dr. Dennis Selkoe for the anti-IDE antibodies and the Institute for Brain Aging and Dementia (University of California, Irvine) for the postmortem AD and control brain specimens. This work was supported by grants to FML from the Alzheimer's Association and by the National Institutes of Health (AG26175 and AG0212982).
PY - 2005/5
Y1 - 2005/5
N2 - Accumulation of amyloid β-protein (Aβ) is a fundamental feature of certain human brain disorders such as Alzheimer's disease (AD) and Down syndrome and also of the skeletal muscle disorder inclusion body myositis (IBM). Emerging evidence suggests that the steady-state levels of Aβ are determined by the balance between production and degradation. Although the proteolytic processes leading to Aβ formation have been extensively studied, less is known about the proteases that degrade Aβ, which include insulin-degrading enzyme (IDE) and neprilysin (NEP). Here we measured the steady-state levels of these proteases as a function of age and brain/muscle region in mice and humans. In the hippocampus, which is vulnerable to AD pathology, IDE and NEP steady-state levels diminish as function of age. By contrast, in the cerebellum, a brain region not marked by significant Aβ accumulation, NEP and IDE levels either increase or remain unaltered during aging. Moreover, the steady-state levels of IDE and NEP are significantly higher in the cerebellum compared to the cortex and hippocampus. We further show that IDE is more oxidized in the hippocampus compared to the cerebellum of AD patients. In muscle, we find differential levels of IDE and NEP in fast versus slow twitch muscle fibers that varies with aging. These findings suggest that age- and region-specific changes in the proteolytic clearance of Aβ represent a critical pathogenic mechanism that may account for the susceptibility of particular brain or muscle regions in AD and IBM.
AB - Accumulation of amyloid β-protein (Aβ) is a fundamental feature of certain human brain disorders such as Alzheimer's disease (AD) and Down syndrome and also of the skeletal muscle disorder inclusion body myositis (IBM). Emerging evidence suggests that the steady-state levels of Aβ are determined by the balance between production and degradation. Although the proteolytic processes leading to Aβ formation have been extensively studied, less is known about the proteases that degrade Aβ, which include insulin-degrading enzyme (IDE) and neprilysin (NEP). Here we measured the steady-state levels of these proteases as a function of age and brain/muscle region in mice and humans. In the hippocampus, which is vulnerable to AD pathology, IDE and NEP steady-state levels diminish as function of age. By contrast, in the cerebellum, a brain region not marked by significant Aβ accumulation, NEP and IDE levels either increase or remain unaltered during aging. Moreover, the steady-state levels of IDE and NEP are significantly higher in the cerebellum compared to the cortex and hippocampus. We further show that IDE is more oxidized in the hippocampus compared to the cerebellum of AD patients. In muscle, we find differential levels of IDE and NEP in fast versus slow twitch muscle fibers that varies with aging. These findings suggest that age- and region-specific changes in the proteolytic clearance of Aβ represent a critical pathogenic mechanism that may account for the susceptibility of particular brain or muscle regions in AD and IBM.
KW - AD
KW - Amyloid β-protein
KW - Aβ
KW - IBM
KW - IDE
KW - Insulin-degrading enzyme
KW - Neprilysin
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U2 - 10.1016/j.neurobiolaging.2004.06.013
DO - 10.1016/j.neurobiolaging.2004.06.013
M3 - Article
C2 - 15708439
AN - SCOPUS:13644266898
SN - 0197-4580
VL - 26
SP - 645
EP - 654
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 5
ER -