Synaptic dysfunction in Alzheimer's disease: the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention

Abstract

The most prevalent form of dementia in the elderly is Alzheimer's disease. A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42 (Aβ42), a small hydrophobic peptide. Unfortunately, attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease. It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach. The accumulation of Aβ42 seems to affect various aspects of physiological cell functions. In this review, we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction, with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release. We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer's disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease. Although the precise mechanisms that trigger synaptic dysfunction are still under investigation, the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.

Keywords: Alzheimer's disease; amyloid-β 42; neurotransmitter release; synaptic dysfunction; synaptic vesicles.

Figure 1

The early effects of amyloid beta (Aβ) on neurotransmission. (A) Under physiological conditions, the amount of synaptic vesicles (SVs) participating in neurotransmitter (NT) release is tightly regulated. Upon neuronal activity, SVs are released from the reserve pool to participate in NT release via CAMKIV-induced Synapsin1 (Snp1) phosphorylation at Ser9. Released SVs dock via soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly and then fuse with the membrane following calcium influx, releasing NT. SVs are pinched of the presynaptic membrane and endocytosed by dynamin1 and are either recycled or tethered back to the reserve pool after protein phosphatase 2A (PP2A)-mediated dephosphorylation of Snp1. (B) Aβ disrupts SV recycling and enhances NT release. Aβ increases the number of SVs available for docking due to sustained calcium/calmodulin kinase IV (CaMKIV)/Snp1 phosphorylation. SV docking is also enhanced due to Aβ-induced disruption of the synaptophysin (Syp1)/VAMP2 complex, enabling Synaptobrevin 2 (VAMP2) to participate in the formation of the SNARE complex. The increased number of docked SVs combined with an Aβ-mediated increase in calcium influx results in abberant NT release. Furthermore, deregulation of endocytosis due to a reduction of dynamin1 levels will eventually deplete the reserve pool of SVs. Notably, the deregulation of activity dependent phosphorylation of Snp1 can be restored by valproic acid (VPA).