Brain activity, drugs could affect Alzheimer's progression

December 21, 2005

The activity of connections among brain cells significantly affects levels of the toxic protein beta-amyloid (Aß) that is a major cause of Alzheimer's disease (AD), researchers have found. Aß is produced by the cleavage of amyloid precursor protein (APP) within brain cells.

Findings suggest that the kind of mental activity people practice or drugs they might take for depression or anxiety could affect their AD risk or the disease progression.

In an article in the December 22, 2005, issue of Neuron, David Holtzman and colleagues detailed studies in which they determined how neuronal activity affected the level of Aß in the "interstitial fluid" (ISF) between cells. The brain damage of AD is caused in considerable part by high levels of Aß in the ISF, where it aggregates into the brain-clogging plaque that kills brain cells.

In studies with mice, they found that stimulating brain cells while sampling ISF revealed a significant increase in Aß levels. Conversely, when they administered drugs that blocked neuronal activity, Aß levels dropped.

Their studies also revealed that Aß appeared to be released from the same kinds of sac-like vesicles in neurons that transport the chemical signals called neurotransmitters that one neuron uses to triggers a nerve impulse in its neighbor. Such vesicles launch their cargoes across the connections called synapses between neurons.

One important question arising from their findings, noted the researchers, is the effect of cognitive activity--such as that produced by an enriched environment--on Aß levels. Both animal and human studies have suggested that such activity affects Aß plaque levels.

"One hypothesis is that enrichment may increase overall synaptic activity in some brain regions and decrease it in others, depending on the environmental alteration," wrote Holtzman and his colleagues. "For example, certain memory tasks in humans simultaneously increase and decrease activity within different brain areas. Increased activity might result in increased susceptibility to Aß deposition if the activated neural circuits contain high levels of human APP expression, thereby increasing Aß release from those pathways. Conversely, if synaptic activity decreases in a brain area that is normally vulnerable to Aß pathology, then there may be reduced Aß deposition as a consequence of enrichment," they wrote.

Overall, the researchers concluded that "these findings are consistent with the possibility that physical and environmental changes resulting in altered neuronal/synaptic activity throughout life can modulate the amount of Aß that accumulates in plaques in a region-dependent manner.

"That synaptic activity and Aß levels are directly linked in vivo may have important treatment implications," they wrote. "Drugs used to treat neuropsychiatric disorders, such as depression or anxiety, among many others, directly influence neurotransmitters, and their receptors, thereby altering synaptic activity," they wrote. "Thus, it is likely that these drugs might influence Aß levels within specified neuronal networks as well. If so, such drugs could potentially influence risk or progression of AD. Understanding the effects of drugs on ISF Aß may enable the design of ways to decrease soluble Aß levels, including synaptotoxic Aß oligomers, in specific brain regions.

"Defining the relationship between normal brain function and the metabolism of a key protein involved in a neurodegenerative disease may provide new clues into the factors that regulate the biology of AD as well as other disorders of the nervous system," they wrote.
John R. Cirrito, Kelvin A. Yamada, Mary Beth Finn, Steven Mennerick, and David M. Holtzman of the Washington University School of Medicine in St. Louis, Missouri; Robert S. Sloviter of the University of Arizona in Tucson, Arizona; Kelly R. Bales, Patrick C. May, Darryle D. Schoepp, and Steven M. Paul of Lilly Research Laboratories in Indianapolis, Indiana. This work was supported by National Institutes of Health grants AG13956 (D.M.H.), AG11355 (D.M.H.), and DA07261 (J.R.C.); an Alzheimer's Association Zenith Award (D.M.H.); MetLife Foundation (D.M.H.); and Eli Lilly and Co. The authors have declared a conflict of interest. K.R.B., P.C.M., D.D.S., and S.M.P. are employees and shareholders of Eli Lilly and Co.

Cirrito et al.: "Synaptic Activity Regulates Interstitial Fluid Amyloid-b Levels In Vivo." Publishing in Neuron, Vol. 48, 913-922, December 22, 2005, DOI 10.1016/j.neuron.2005.10.028

Cell Press

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