Different forms of amyloid beta in Alzheimer's disease harm neurons in different ways
Jun 1, 2006 - 1:05:37 PM

Researchers at UC Irvine have shown that different forms of amyloid beta lead to neural damage in different ways, leading to an increasingly complex view of amyloid toxicity in the Alzheimer brain. The finding could modify the way therapeutic approaches for the treatment of Alzheimer’s disease are designed.

The researchers studied the effects of different forms of the amyloid beta peptide on human brain cells. Amyloid beta accumulation is one of two hallmarks of Alzheimer’s disease and is considered a major target for researchers looking into therapies for the treatment of the disease. After death, most amyloid beta found in the brains of Alzheimer’s patients is in fibrillar form – long, insoluble fibers bound together in deposits called senile plaques; however, there are also soluble forms of amyloid beta, or oligomers, that may decisively contribute to neural degeneration.

The experiments conducted at UCI showed that the soluble forms of amyloid beta are much more toxic and lead to neuronal death in as little as 12 hours. The fibrillar form, meanwhile, does not actually kill the neurons, but slowly, over a period of 10 or more days, renders them useless.

Not known is whether the soluble amyloid beta in the Alzheimer brain eventually turns into the fibrillar kind, or whether the two are completely different.

“These findings are quite significant because, although both fibrils and oligomers may contribute to dementia, they do so in very different ways over different time spans,” said Jorge Busciglio, an assistant professor of neurobiology and behavior. “This complexity of the amyloid beta species will require more sophisticated therapeutic approaches. For example, it might be dangerous to create compounds that target fibrillar amyloid and try to break them up, because if the fibers dissolve into the soluble form, that could actually speed up cell death and the onset of dementia rather than treat it.”

Atul Deshpande, a graduate student in Busciglio’s laboratory, tested one preparation of fibrillar amyloid beta and two soluble ones, which resemble the types found in the brains of Alzheimer’s patients. In less than 12 hours, the human neurons exposed to one of the two soluble forms started to die. Most of the cells were dead after 24 hours. The cells exposed to the other soluble form took about five times longer to die. In contrast, the brain cells treated with the fibrillar form slowly degenerated. The axons and dendrites in the cells became twisted and rendered the cell functionally useless. For the most part, however, the cells did not die.

According to the scientists, previous research has shown that the brain levels of soluble amyloid beta appear to correlate better with severity of cognitive impairment than the number and density of plaques found in the brain. Then, the more soluble beta amyloid is present, the more severe and rapid the onset of the disease.

Researchers now will have to determine why the soluble form of beta amyloid is so much more toxic. One theory is it binds to neuronal connections, or gateways into the cell, and gives soluble amyloid beta easier, quicker access into the neuron. The UCI research also showed that the soluble form quickly impairs the function of mitochondria, the cells’ energy generators. Brain cells consume more energy than any other cell in the body. If that energy source dies, the cells die as well.

Alzheimer’s disease is a progressive neurodegenerative disorder, affecting 4.5 million to 5 million adults in the United States. If no effective therapies are developed, it is estimated that 13 million Americans will be afflicted with the disease by 2050. It is the third-most-expensive disease to treat and the third-leading cause of death, behind cancer and coronary heart disease.

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