Neuronal Activity and Beta Amyloid Levels

Aβ is a protein of unknown function that is secreted by brain cells normally but accumulates in toxic forms outside of brain cells in the progression of Alzheimer’s disease. It is known that eventual accumulation of toxic Aβ is related to the levels of released Aβ throughout life, but the processes governing Aβ release from cells are poorly understood. Better understanding could lead to early intervention in the disease, before toxic accumulation can occur. Inversely, exploring the effects of released Aβ protein on the function of brain cells should lead us to better understand what goes awry in neuronal signaling during disease progression. The goals of the proposed studies are to test a negative feedback hypothesis of Aβ release and effects. Neurons normally communicate by releasing chemical messenger (transmitter) from tiny, membrane-bound packages, or vesicles, by fusion of these vesicles with the cell membrane. These packages are re-used by a process of membrane retrieval from the cell surface. Preliminary results demonstrate that somehow the process of vesicle use and retrieval (normal neuronal communication) causes the appearance of more Aβ outside of brain cells. The first aim is to test the idea that vesicle retrieval is directly important for Aβ release from neurons. This result would support a general hypothesis by which the process of membrane retrieval, driven by neuronal communication, normally retrieves the precursor for Aβ along with vesicle membrane. The precursor gets sorted into a compartment inside the cell separate from the vesicle, and the precursor, when in this intracellular compartment, is cleaved to Aβ. The Aβ is then secreted by the cell from this separate compartment. The idea that neuronal communication itself indirectly drives Aβ release may influence strategies for slowing the release of Aβ and preventing toxic Aβ formation. The second aim explores the general question “Once Aβ is released, what does it do?” Dr. Mennerick will test the hypothesis that Aβ feeds back to dampen the ability of brain cells to communicate with each other. If so, this could directly cause neuronal dysfunction during disease progression. Aβ regulation of neuronal communication could have a normal function, which turns pathological in the presence of excessive Aβ levels.