Age- and region-dependent alterations in Aβ-degrading enzymes

Implications for Aβ-induced disorders

Antonella Caccamo, Salvatore Oddo, Michael C. Sugarman, Yama Akbari, Frank M. LaFerla

Research output: Contribution to journalArticle

241 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)645-654
Number of pages10
JournalNeurobiology of Aging
Volume26
Issue number5
DOIs
StatePublished - May 2005
Externally publishedYes

Fingerprint

Insulysin
Neprilysin
Alzheimer Disease
Enzymes
Inclusion Body Myositis
Hippocampus
Muscles
Cerebellum
Brain
Peptide Hydrolases
Slow-Twitch Muscle Fibers
Cerebellar Diseases
Serum Amyloid A Protein
Brain Diseases
Muscular Diseases
Down Syndrome
Skeletal Muscle
Pathology

Keywords

  • AD
  • Amyloid β-protein
  • IBM
  • IDE
  • Insulin-degrading enzyme
  • Neprilysin

ASJC Scopus subject areas

  • Clinical Neurology
  • Biological Psychiatry
  • Developmental Neuroscience
  • Neurology
  • Psychology(all)

Cite this

Age- and region-dependent alterations in Aβ-degrading enzymes : Implications for Aβ-induced disorders. / Caccamo, Antonella; Oddo, Salvatore; Sugarman, Michael C.; Akbari, Yama; LaFerla, Frank M.

In: Neurobiology of Aging, Vol. 26, No. 5, 05.2005, p. 645-654.

Research output: Contribution to journalArticle

Caccamo, Antonella ; Oddo, Salvatore ; Sugarman, Michael C. ; Akbari, Yama ; LaFerla, Frank M. / Age- and region-dependent alterations in Aβ-degrading enzymes : Implications for Aβ-induced disorders. In: Neurobiology of Aging. 2005 ; Vol. 26, No. 5. pp. 645-654.
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