Trans-Synaptic Spread of Amyloid-ß in Alzheimer's Disease: Paths to ß-Amyloidosis.

ABSTRACT

Neuronal activity has a strong causal role in the production and release of the neurotoxic ß-amyloid peptide (Aß). Because of this close link, gradual accumulation of Aß into amyloid plaques has been reported in brain areas with intense neuronal activity, including cortical regions that display elevated activation at resting state. However, the link between Aß and activity is not always linear and recent studies report exceptions to the view of "more activity, more plaques." Here, we review the literature about the activity-dependent production of Aß in both human cases and AD models and focus on the evidences that brain regions with elevated convergence of synaptic connections (herein referred to as brain nodes) are particularly vulnerable to Aß accumulation. Next, we will examine data supporting the hypothesis that, since Aß is released from synaptic terminals, ß-amyloidosis can spread in AD brain by advancing through synaptically connected regions, which makes brain nodes vulnerable to Aß accumulation. Finally, we consider possible mechanisms that account for ß-amyloidosis progression through synaptically linked regions.