APP-dependent changes in vesicle refilling following Aß and tau elevation

Background Research has found that brain changes associated with Alzheimer's may occur decades before outward symptoms appear. These changes include damage to nerve cell synapses – the specialized connections that nerve cells use to send signals to one another and communicate. Early synaptic damage can lead to memory loss and other forms of cognitive decline in Alzheimer's. Moreover, according to recent studies, synaptic damage may be linked to amyloid precursor protein (APP). APP has long been known as the 'parent' molecule of beta-amyloid, a protein fragment that contributes to hallmark plaques in the Alzheimer's brain. However, APP has also been shown to promote activities of beta-amyloid and tau (another dementia-related protein) that lead to synaptic damage and memory loss. In initial research, Dr. Erica Acquarone and colleagues examined brain tissue from mice engineered with (1) high brain levels of beta-amyloid and tau and (2) APP deleted in some of their nerve cells. They observed that by deleting APP in 'presynaptic' nerve cells (or nerve cells that send signals toward a synapse), they could prevent tau- and amyloid-related synaptic (communication signals) damage in the brain tissue. The researchers also examined the loss of presynaptic APP positively impacted a key mechanism of synaptic function called 'vesicle refilling.' Vesicles are specialized, pouch-like structures that carry molecules to synapses – molecules necessary for cell-to-cell communication. Once a vesicle releases its molecules, it must be 'refilled' and repeat the process again and again. This refilling function can become disturbed in Alzheimer's, often by small accumulations of beta-amyloid and tau called oligomers. But the investigators found that by deleting presynaptic APP, they could prevent abnormal vesicle refilling in the brain tissue.