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S3‐04–04: Regulation of APP trafficking and processing in neurons
Author(s) -
Suzuki Toshiharu
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.395
Subject(s) - golgi apparatus , microbiology and biotechnology , cytoplasm , amyloid precursor protein , phosphorylation , signal transducing adaptor protein , intracellular , alpha secretase , glycosylation , mutant , amyloid precursor protein secretase , chemistry , biology , biochemistry , endoplasmic reticulum , alzheimer's disease , gene , pathology , medicine , disease
Background: Amyloid beta (A ) peptide accumulation is known to be an important event in the progression of Alzheimer’s disease (AD). Sequential cleavage of the amyloid precursor protein (APP) by two aspartyl proteases known as and -secretase, results in the production of A . Cyclindependent kinase 5 (Cdk5) has been implicated in both physiological and pathological processes in neurons. P35, a well-characterized, neuronalspecific activator of Cdk5, is cleaved into p25 by calpain. Generation of p25 is largely associated with neurotoxic conditions. Methods: We have previously characterized inducible p25Tg mice that exhibit progressive neurodegeneration, neuronal loss, reactive astrogliosis, and impaired learning following 5-6 weeks of induction. A levels are elevated in p25Tg mice as early as 2-3 weeks following p25 induction, a timepoint at which neurodegeneration is not apparent. Additionally, p25Tg mice exhibit intraneuronal and extracellular accumulation of A . Results: Interestingly, -secretase (BACE1) levels and activity are elevated in the p25Tg mice. We have evidence suggesting that genetic deletion of BACE1 can ameliorate the neurodegenerative phenotype associated with the p25Tg mice, and rescue the learning impairment. Conclusions: These observations indicate that elevated A levels play an important role in p25-induced neurotoxicity and learning impairments. Moreover, our data supports a role for BACE1 inhibition as a potential therapeutic strategy to treat AD.