The activity of connections among brain cells significantly affects levels of the toxic protein beta-amyloid that is a major cause of Alzheimer's disease.

The protein beta-amyloid is produced by the cleavage of amyloid precursor protein 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 Alzheimer's disease risk or the disease progression.

In an article, published in the journal Neuron, David Holtzman and colleagues detailed studies in which they determined how neuronal activity affected the level of protein beta-amyloid in the "interstitial fluid" (ISF) between cells.

The brain damage of Alzheimer's disease is caused in considerable part by high levels of beta-amyloid 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 protein beta-amyloid levels. Conversely, when they administered drugs that blocked neuronal activity, protein beta-amyloid levels dropped.

Their studies also revealed that protein beta-amyloid 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 protein beta-amyloid levels. Both animal and human studies have suggested that such activity affects beta-amyloid 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 protein beta-amyloid deposition if the activated neural circuits contain high levels of human amyloid precursor protein expression, thereby increasing protein beta-amyloid release from those pathways. Conversely, if synaptic activity decreases in a brain area that is normally vulnerable to protein beta-amyloid pathology, then there may be reduced protein beta-amyloid 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 protein beta-amyloid that accumulates in plaques in a region-dependent manner.

" That synaptic activity and protein beta-amyloid 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 beta-amyloid levels within specified neuronal networks as well. If so, such drugs could potentially influence risk or progression of Alzheimer's disease. Understanding the effects of drugs on ISF beta-amyloid may enable the design of ways to decrease soluble beta-amyloid levels, including synaptotoxic beta-amyloid 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 Alzheimer's disease as well as other disorders of the nervous system," they wrote.

Source: Neuron, 2005


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