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P1‐489: Insulin‐degrading enzyme: A possible “dead‐end” chaperone for amyloid peptides
Author(s) -
Tullio Matias B.,
Fernandez Gamba Agata C.,
Llovera Ramiro,
Morelli Laura,
Castaño Eduardo M.
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.2008.05.1072
Subject(s) - insulin degrading enzyme , guanidine , biochemistry , chemistry , proteolysis , microbiology and biotechnology , enzyme , immunoprecipitation , blot , biology , gene
chondrial dysfunction is one of the key intracellular lesions associated with the pathogenesis of Alzheimer’s disease (AD). However, the pathophysiological mechanisms leading to the dysfunction of mitochondria in AD are not well understood. In particular, the functional changes of mitochondria in living animals have not been elucidated. Methods: Accumulation of amyloid(A ) into senile plaques is a hallmark feature of AD, which contributes to alterations in neuronal structure and function. Here we use multiphoton microscopy to investigate the physiology and pathology of mitochondria in the brains of living mice (APPswe, PSEN1dE9), to explore the relationship between A plaques and mitochondrial morphology, function, and trafficking. We screened and characterized a variety of fluorescent probes to allow the measurement of mitochondria structure and function in combination with multiphoton imaging in living mice. Lenti-virus mediated mitochondrial-targeting GFP (mitoGFP) expression was used to visualize mitochondrial structure in neurons in somatosensory cortex. The mitochondrial membrane potential sensitive dye, MitoTracker Red CMXRos was used to measure the functional state of the mitochondria. Results: Multiphoton imaging of mitoGFP-labeled mitochondria in 7-month old transgenic mice showed normal morphology of mitochondria comparing to age-matched control mice. However, MitoTracker Red CMXRos revealed disrupted mitochondrial function in the transgenic mice. A profound deficit in mitochondrial membrane potential extended 25 m from the edges of dense-core plaques. The reduction of mitochondrial membrane potential was associated with neuritic curvature, spine loss, and dystrophy, suggesting the initiation of neurodegeneration in the immediate vicinity of senile plaques. Conclusions: These results demonstrate that plaques are a focal source of toxicity in the brain. The observed reduction in mitochondrial function suggests a mechanism to account for the neural network disruptions and subsequent behavioral deficits observed in the APP mice, and may represent a therapeutic target for restoration of neuronal function.