Amyloid-beta peptide (Ab) is considered a key protein in the pathogenesis of Alzheimer’s disease (AD) because of its neurotoxicity and capacity to form characteristic insoluble deposits known as senile plaques. Ab derives from amyloid-b protein precursor (AbPP), whose proteolytic processing generates several fragments including Ab peptides of various lengths. The normal function of AbPP and its fragments remains poorly understood. While some fragments has been suggested to have a function in normal physiological cellular processes, Ab has been widely considered as a “garbage” fragment that becomes toxic when it accumulates in the brain, resulting in impaired synaptic function and memory. Ab is produced and released physiologically in the healthy brain during neuronal activity. In the last 10 years, we have been investigating whether Ab plays a physiological role in the brain. We first demonstrated that picomolar concentrations of a human Ab42 preparation enhanced synaptic plasticity and memory in mice. Next, we investigated the role of endogenous Ab in healthy murine brains and found that treatment with a specific antirodent Ab antibody and an siRNA against murine AbPP impaired synaptic plasticity and memory. The concurrent addition of human Ab42 rescued these deficits, suggesting that in the healthy brain, physiological Ab concentrations are necessary for normal synaptic plasticity and memory to occur. Furthermore, the effect of both exogenous and endogenous Ab was seen to be mediated by modulation of neurotransmitter release and alpha7-nicotinic receptors. These findings need to be taken into consideration when designing novel therapeutic strategies for AD.
|Titolo:||Amyloid-beta Peptide: Dr. Jekyll or Mr. Hyde?|
|Data di pubblicazione:||2013|
|Appare nelle tipologie:||1.1 Articolo in rivista|