Introduction - Abnormally high levels of amyloid-β peptide (Aβ) are likely to play a major role in Alzheimer’s disease (AD) pathogenesis. However, Aβ is also needed for formation of memory and its cellular surrogate long-term potentiation (LTP), and has a positive modulatory effect on these phenomena when it is administered at low picomolar concentrations resembling the physiological content of the peptide in the brain. To better understand why and how a protein involved in synaptic plasticity in the healthy brain, at some point, accumulates leading to AD, we investigated the relationship between low picomolar Aβ and events normally occurring at the synaptic level. In particular, we focused on the crosstalk between Aβ and cGMP, which is known play a key role both in pre- and post-synaptic mechanisms of plasticity and in the conversion from early- to late-long-term- LTP. Methods - We first investigate whether an increase of cGMP levels by phosphodiesterase-5 inhibitors (PDE5-Is), such as sildenafil and vardenafil, might affect Aβ levels in Neuro-2a (N2a) cells and hippocampal slices. We also evaluated whether PDE5-Is might modify Amyloid Precursor Protein (APP) expression and the interaction between APP and the β-site APP cleaving enzyme-1 (BACE-1), by the OptiCAB assay in primary hippocampal neurons. Finally, we performed electrophysiological experiments on hippocampal slices and behavioral studies (novel object recognition) to analyze whether the vardenafil-induced enhancement of LTP and memory was still present when blocking Aβ function. Results - We have demonstrated that the enhancement of cGMP levels induces a parallel release of Aβ due to a change in the approximation of amyloid precursor protein (APP) and the β-site APP cleaving enzyme 1 (BACE1). In addition, electrophysiological and behavioral studies showed that blocking Aβ function - by using anti-murine Aβ antibodies or APP knock-out mice - prevents the cGMP-dependent enhancement of LTP and memory, suggesting that cGMP acts through Aβ to boost LTP and memory. Conclusions - We found a tight relationship between cGMP and Aβ, demonstrating that cGMP regulates Aβ production and function. This might be useful to better understand the mechanism of action of drugs increasing cGMP levels, such as PDE5-Is, that might exert their cognitive-enhancing effects via a positive modulation of Aβ in the brain. Most importantly, these experiments stress the relevance of fully understanding the physiological role of Aβ to design effective and safe approaches to AD therapy, as Aβ lowering therapies might lead to memory worsening instead of ameliorating it.
|Titolo:||cGMP and Aβ crosstalk: relevance of physiological synaptic mechanisms for Alzheimer’s disease. In: Shaping Glutamatergic transmission by intrinsic mechanisms and cross-talking neurotransmitters: from synaptic function to synaptic dysfunction.|
|Data di pubblicazione:||2017|
|Appare nelle tipologie:||4.2 Abstract in Atti di convegno|