Abstract
Alzheimer’s disease (AD) is the most common form of senile dementia. Identification of genes causally associated with familial Alzheimer’s disease (FAD) advanced our understanding of the molecular mechanisms of AD pathogenesis. However, FAD is much less common than sporadic Alzheimer’s disease (SAD), which constitutes the majority of cases. Despite its similar pathology (albeit at a later age of onset), SAD is not linked to mutations in FAD-associated genes. In both FAD and SAD, the generation and oligomerization of amyloid β (Aβ) peptide play central roles in neurotoxicity, but it remains unclear how qualitative and quantitative alterations in Aβ occur in SAD patients in the absence of causative mutations. The predominant risk factor for SAD is aging, suggesting that some as-yet-unknown alterations in the aged brain augment the amyloidogenic metabolism of APP and promote the neural toxicity of Aβ oligomers. In this chapter, we discuss potential biochemical changes in amyloid β precursor protein (APP) and proteins related to APP metabolism and function in the aged brain. APP axonal transport, membrane microlocalization and metabolism, including generation of Aβ in neurons, are regulated by interactions with several cytoplasmic proteins and phosphorylation of the APP cytoplasmic region. Age-related decline or aberration in the regulation of APP transport, localization and metabolism may induce generation of altered Aβ. Here, we focus on APP phosphorylation at threonine 668 in the cytoplasmic domain and the roles of APP regulatory proteins, including X11-like (X11L), JIP1, kinesin-1, and Alcadein, on the regulation of APP metabolism and intracellular trafficking.
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Acknowledgements
We are thankful to Prof. Nozomu Mori (Nagasaki University) and Prof. Inhee Mook-Jung (Seoul National University) for giving us this opportunity to write this review. This work was supported in part by Grant-in-Aid for Scientific Research 26293010 (to T.S.) and 24790062 (to S.H.) from MEXT, Japan, and in part by the Asian Core Program of the JSPS, Japan. S.H. was supported by the Bilateral Joint Research Projects of the JSPS.
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Suzuki, T., Kimura, A., Chiba, K., Nakaya, T., Hata, S. (2015). Brain Aging as a Cause of Alzheimer’s Disease. In: Mori, N., Mook-Jung, I. (eds) Aging Mechanisms. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55763-0_18
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DOI: https://doi.org/10.1007/978-4-431-55763-0_18
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