Genomic triplication of the alpha-synuclein gene recently has been associated with familial Parkinson's disease in the Spellman-Muenter kindred. Here, we present an independent family, of Swedish-American descent, with hereditary early-onset parkinsonism with dementia due to alpha-synuclein triplication. Brain tissue available from affected individuals in both kindreds provided the opportunity to compare their clinical, pathological, and biochemical phenotypes. Of note, studies of brain mRNA and soluble protein levels demonstrate a doubling of alpha-synuclein expression, consistent with molecular genetic data. Pathologically, cornu ammonis 2/3 hippocampal neuronal loss appears to be a defining feature of this form of inherited parkinsonism. The profound implications of alpha-synuclein overexpression for idiopathic synucleinopathies are discussed.

Extensive β-amyloid (Aβ) deposits in brain parenchyma in the form of senile plaques and in blood vessels in the form of amyloid angiopathy are pathological hallmarks of Alzheimer's disease (AD). The mechanisms underlying Aβ deposition remain unclear. Major efforts have focused on Aβ production, but there is little to suggest that increased production of Aβ plays a role in Aβ deposition, except for rare familial forms of AD. Thus, other mechanisms must be involved in the accumulation of Aβ in AD. Recent data shows that impaired clearance may play an important role in Aβ accumulation in the pathogenesis of AD. This review focuses on our current knowledge of Aβ-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), insulin-degrading enzyme (IDE), angiotensin-converting enzyme (ACE), and the plasmin/uPA/tPA system as they relate to amyloid deposition in AD.

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J. Neurochem. (2010) 115, 47–57. Abstract The brain steady state level of β‐amyloid (Aβ) is determined by the balance between its production and removal, the latter through egress across blood and CSF barriers as well as Aβ degradation. The major Aβ‐degrading enzymes are neprilysin (NEP), insulin‐degrading enzyme (IDE), and endothelin‐converting enzyme (ECE‐1). Although evidence suggests that NEP is down‐regulated in Alzheimer’s disease (AD), the role of IDE and ECE in the Aβ accumulation in aging and dementia remains less certain. In this study, we examined mRNA and protein expression, as well as biological activity of NEP, IDE, and ECE‐1 in human frontal cortex by real‐time RT‐PCR for mRNA, immunoblotting for protein, and highly sensitive and specific fluorescence assays for activity. The relationships between Aβ‐degrading enzymes and pathologic measures and clinical features were also assessed. The results showed that NEP mRNA, protein level, and activity were decreased in AD compared with normal controls with no cognitive impairment (NCI). In contrast, IDE activity was unchanged, but there was higher expression of IDE mRNA, indicating a possible compensatory reaction because of deficits in activity. ECE‐1 expression in AD brain showed no significant difference compared with age‐matched controls. Correlation analyses suggested that NEP expression was correlated with Aβ accumulation and clinical diagnosis, being lower in AD than in no cognitive impairment. In contrast, neither IDE nor ECE‐1 correlated with Aβ or clinical diagnosis. These findings provide additional support for NEP as the major protease involved in Aβ degradation and suggest its possible therapeutic targeting in AD.