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P1‐239: Disruptions of endoplasmic reticulum and mitochondria prime mTOR suppression in low molecular weight Aβ‐induced autophagy
Author(s) -
Chuen Raymond,
Chang Chung,
Cheung Yuen Ting,
Zhang Natalie Qishan,
Ling Hung Clara Hui,
Wan Lai Cora Sau,
Yu Man Shan
Publication year - 2010
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.2010.05.790
Subject(s) - autophagy , autophagosome , endoplasmic reticulum , microbiology and biotechnology , lysosome , vacuole , biology , organelle , mitochondrion , vdac1 , programmed cell death , biochemistry , apoptosis , cytoplasm , escherichia coli , bacterial outer membrane , gene , enzyme
Background: Recent studies have demonstrated that soluble Ab dimers isolated from AD brains inhibit long-term potentiation (LTP), reduce dendritic spine density in vitro and upon direct injection into the brain of normal rats disrupt memory (Shankar et al., 2008). In the current study we evaluated the acquisition performance of PSAPP mice in a Morris water maze, and searched for Ab oligomers in brains of PSAPP transgenic mice to determine whether the soluble Ab in the transgenic mice has similar biochemical properties to human Ab extracted from AD brains. Methods: Wild type (wt) and heterozygous PSAPP mice were trained in the Morris water maze (4 trials/day for 9 days) and the latency to reach the platform was recorded for each trial. Soluble Ab oligomers were measured from the brains of the PSAPP transgenic mice using a sensitive immunoprecipitation/Western blotting protocol after homogenizing the whole cerebra in Tris-buffered saline. Results: Aged mice (>12 months) exhibit an increase in plaque load and have deficits in the Morris water maze. We observe high levels of Ab dimers in young transgenic mice (2-3 months of age) which decline before increasing again from 7-12 months. No overt cognitive deficits were seen in the 3 and 9 month old mice suggesting that dimers need to reach a critical threshold before memory deficits, in this specific cognitive paradigm, are observed. Both Ab1-40 and Ab1-42 are present in soluble extracts from PSAPP brains. However, in human AD brains Ab1-42 is the predominant species in the soluble extract. Conclusions: These studies demonstrate that the biochemical and, potentially, the pathophysiological properties of Ab in young PSAPP mice are different from that of Ab extracted from elderly human AD patients.