Premium
P1‐250: Potent inhibition of ACE leads to Alzheimer‐like pathology in APP transgenic mouse brain
Author(s) -
Zou Kun,
Liu Shuyu,
Liu Junjun,
Tanabe Chiaki,
Maeda Tomoji,
Michikawa Makoto,
Komano Hiroto
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.2010.05.801
Subject(s) - neuroprotection , neurodegeneration , genetically modified mouse , ace inhibitor , angiotensin converting enzyme , alzheimer's disease , medicine , pathogenesis , pharmacology , endocrinology , ventricle , transgene , disease , chemistry , biochemistry , blood pressure , gene
Background: It is now widely accepted that endocytic dysfunction is intimately involved in early-stage Alzheimer’s disease (AD) pathology, such as the accumulation of b-amyloid precursor protein (APP) in enlarged early endosomes. However, it remains unclear how endocytic dysfunction is induced in an age-dependent manner. We have previously shown that the interaction between dynein-dynactin complexes is clearly attenuated in aged monkey brains, suggesting that dynein-mediated transport dysfunction exists in aged brains. In the present study, we assessed our hypothesis that the dysfunction of dynein-mediated transport would be responsible for endocytic dysfunction leading to AD pathology. Methods: We examined immunohistochemistry and westernblot by using young and aged monkey brains to investigate age-related endocytic pathology. We also examined RNAi studies to assess whether dynein dysfunction can reproduce endocytic pathology as seen in aged monkey brains. Results: Immunohistochemical and westernblot analyses revealed that age-dependent endocytic pathology was accompanied by an increase in Rab GTPases in aged monkey brains. We also demonstrated that siRNA-induced dynein dysfunction reproduced the endocytic pathology accompanied by increased Rab GTPases seen in aged monkey brains. Moreover, it also resulted in endosomal APP accumulation characterized by increased b-site cleavage, and the amount of intracellular Ab was increased. Conclusions: These findings suggest that dynein dysfunction may underlie age-dependent endocytic dysfunction via the upregulation of Rab GTPases, leading to early stage of AD pathology.