β -Amyloid: A Disease Target or a Synaptic Regulator Affecting Age-Related Neurotransmitter Changes?

The amyloid cascade hypothesis sustains that beta-amyloid (Aβ) is the main pathogenetic factor of Alzheimer's Disease (AD). Although the direct and indirect neurotoxic role of Aβ are unchallenged, recent findings suggest that the peptide may have so far unforeseen physiological roles. In this regard, the observations showing the ability of Aβ to exert synaptic activities in absence of neurotoxicity are very intriguing. In particular, the peptide is able to affect synaptic transmission of different neurotransmitter systems in key brain areas that regulate executive and cognitive functions, an observation that points Aβ as a new neuromodulator. However, in a pathological context, Aβ may drive functional alterations of several neurotransmitter systems in the early phases of the disease, in turn producing subtle cognitive and behavioural disturbances in addition and before the well known neurodegenerative events. On the other hand, advancing age is the most significant risk factor for the development of AD. In fact, during aging increased Aβ levels have been reported. Moreover, several neurotransmitter systems undergo age-related changes in parallel to a decline of cognitive functions. However, the putative neuromodulatory role of Aβ in the context of aging is nowadays unknown. For these reasons, future studies about the spectrum of action of Aβ (brain areas and neurotransmitter systems affected) are particularly interesting since may suggest new therapeutic targets in order to sustain those functions which may be altered during aging.