Authors: Moon, Minho | Hong, Hyun-Seok | Nam, Dong Woo | Baik, Sung Hoon | Song, Hyundong | Kook, Sun-Young | Kim, Yong Soo | Lee, Jeewoo | Mook-Jung, Inhee
Article Type:
Research Article
Abstract:
One of the major hallmarks of Alzheimer's disease (AD) is the extracellular deposition of amyloid-β (Aβ) as senile plaques in specific brain regions. Clearly, an understanding of the cellular processes underlying Aβ deposition is a crucial issue in the field of AD research. Recent studies have found that accumulation of intraneuronal Aβ (iAβ) is associated with synaptic deficits, neuronal death, and cognitive dysfunction in AD patients. In this study, we found that Aβ deposits had several shapes and sizes, and that iAβ occurred before the formation of extracellular amyloid plaques in the subiculum of 5XFAD mice, an animal model of
…AD. We also observed pyroglutamate-modified Aβ (N3pE-Aβ), which has been suggested to be a seeding molecule for senile plaques, inside the Aβ plaques only after iAβ accumulation, which argues against its seeding role. In addition, we found that iAβ accumulates in calcium-binding protein (CBP)-free neurons, induces neuronal death, and then develops into senile plaques in 2-4-month-old 5XFAD mice. These findings suggest that N3pE-Aβ-independent accumulation of Aβ in CBP-free neurons might be an early process that triggers neuronal damage and senile plaque formation in AD patients. Our results provide new insights into several long-standing gaps in AD research, namely how Aβ plaques are formed, what happens to iAβ and how Aβ causes selective neuronal loss in AD patients.
Show more
Keywords: 5XFAD mice, Alzheimer's disease, amyloid plaque, calcium-binding proteins, intraneuronal Aβ, pyroglutamate-modified Aβ
DOI: 10.3233/JAD-2011-111778
Citation: Journal of Alzheimer's Disease,
vol. 29, no. 3, pp. 615-628, 2012
Price: EUR 27.50