Abstract

Intracellular and extracellular accumulation and aggregation of amyloid beta (Aβ) is linked to neuronal and synaptic pathology of Alzheimer’s disease (AD). A part of being involved in this pathological process, there are growing evidences suggesting an essential role of naturally secreted Aβ in synaptic plasticity, the process that underlies learning and memory. The aim of the present study was to investigate the role of endogenous Aβ in presynaptic plasticity and especially its effect on presynaptic release apparatus including the active zone cytomatrix that spatially and functionally coordinates neurotransmitter release. In our work we used primary cortical neurons as convenient cellular model accessible for different pharmacological modulations, also allowing consecutive, simultaneous immunocytochemical and functional analysis. Interference with natural production and clearance of endogenously secreted Aβ or addition of physiologically relevant concentration (in pM range) of synthetic Aβ peptide, confirmed its important role in the regulation of presynaptic release. This change in presynaptic efficacy was connected with an extensive remodelling of presynaptic scaffolds, SV proteins and recruitment of VDCCs into release sites. Furthermore, our data clearly demonstrated an indispensable role of the functional alpha7nAChRs and Cav2.2 type of VDCCs in Aβ driven presynaptic potentiation. Taken together, our study provides new mechanistic insights into Aβ synaptic function in normal, physiological conditions. This could help to better understand the effects of its chronic elevation on synaptic failure preceding the cognitive decline in AD and to design more effective and safe approaches to AD therapy.

Kontaktinformation

Dr Vesna Lazarevic, Assistant professor in molecular neuropharmacology
Department of Clinical Neuroscience
Karolinska Institutet
E-post: Vesna.lazarevic@ki.se

Värd

Kalicharan Patra, PhD, Institutionen för neurokemi