Intracellular Amyloid-β Accumulation in Calcium-Binding Protein-Deficient Neurons Leads to Amyloid-β Plaque Formation in Animal Model of Alzheimer's Disease

One of the major hallmarks of Alzheimer's disease (AD) is the extracellular deposition of amyloid-beta (A beta) as senile plaques in specific brain regions. Clearly, an understanding of the cellular processes underlying A beta deposition is a crucial issue in the field of AD research. Recent studies have found that accumulation of intraneuronal A beta (iA beta) is associated with synaptic deficits, neuronal death, and cognitive dysfunction in AD patients. In this study, we found that A beta deposits had several shapes and sizes, and that iA beta occurred before the formation of extracellular amyloid plaques in the subiculum of 5XFAD mice, an animal model of AD. We also observed pyroglutamate-modified A beta (N3pE-A beta), which has been suggested to be a seeding molecule for senile plaques, inside the A beta plaques only after iA beta accumulation, which argues against its seeding role. In addition, we found that iA beta 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-A beta-independent accumulation of A beta 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 A beta plaques are formed, what happens to iA beta and how A beta causes selective neuronal loss in AD patients.