Eta-amyloid discovered in Alzheimer's adds new piece to the complex puzzle

Alzheimer's disease is often characterized by the appearance of protein aggregates that are toxic in the brain. For over 30 years it has been known that protein fragments called beta-amyloid peptides generate these insoluble deposits.

Now an international team of researchers led by Professor Christian Haass and Dr. Michael Willem, both at Ludwig Maximilians University Munich, have characterized a new protein aggregate at play that needs to be carefully considered by Alzheimer's drug investigators.

"A second mode of APP cleavage exists, which involves a previously unknown cleavage and generates an alternative peptide," says Haass.

"The processing pathway that produces it has been overlooked for 30 years. This is because investigators including myself have focused their attention on elucidating the origin of the beta-amyloid and on attempts to cure Alzheimer's by inhibiting production of this peptide," Haass adds, referring to their recently named protein fragment taking the Greek letter eta--amyloid-η.

Beta-amyloid deposits in the brain make nerve cells hyperactive. The action of amyloid-η--produced by the same precursor protein (APP) through the sequential action of two enzymes--has the opposite antagonizing effect on neuronal activity, and this fine balance needs to be accounted for.

Haass and Willem's findings, published in the journal Nature, have direct implications for clinical trials that currently all target beta-amyloid. The team has exemplified a clinical trial involving pharmacological inhibition of beta-secretase, a proteolytic enzyme that initiates the release of the toxic beta-amyloid from APP. Its primary mechanism is to reduce levels of beta-amyloid in a protective way to reduce memory loss; however, the researchers show this inhibition also greatly increases amyloid-η.

"This could result in attenuation of neuronal activity and might therefore compromise brain function," says Haass. He emphasized to the investigators the need to look out for unexpected side effects of experimental drugs.

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