| First Author | Gulisano W | Year | 2019 |
| Journal | J Neurosci | Volume | 39 |
| Issue | 30 | Pages | 5986-6000 |
| PubMed ID | 31127002 | Mgi Jnum | J:277444 |
| Mgi Id | MGI:6333070 | Doi | 10.1523/JNEUROSCI.0163-19.2019 |
| Citation | Gulisano W, et al. (2019) Neuromodulatory Action of Picomolar Extracellular Abeta42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory. J Neurosci 39(30):5986-6000 |
| abstractText | Failure of anti-amyloid-beta peptide (Abeta) therapies against Alzheimer's disease (AD), a neurodegenerative disorder characterized by high amounts of the peptide in the brain, raised the question of the physiological role of Abeta released at low concentrations in the healthy brain. To address this question, we studied the presynaptic and postsynaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric Abeta42 (oAbeta42) on synaptic glutamatergic function in male and female mice. We found that 200 pm oAbeta42 induces an increase of frequency of miniature EPSCs and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level. oAbeta42 also produced postsynaptic changes as shown by an increased length of postsynaptic density, accompanied by an increased expression of plasticity-related proteins such as cAMP-responsive element binding protein phosphorylated at Ser133, calcium-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for Abeta in synaptic tagging. These changes resulted in the conversion of early into late long-term potentiation through the nitric oxide/cGMP/protein kinase G intracellular cascade consistent with a cGMP-dependent switch from short- to long-term memory observed in vivo after intrahippocampal administration of picomolar amounts of oAbeta42 These effects were present upon extracellular but not intracellular application of the peptide and involved alpha7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oAbeta42 in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high Abeta levels in the AD brains.SIGNIFICANCE STATEMENT High levels of oligomeric amyloid-beta42 (oAbeta42) induce synaptic dysfunction leading to memory impairment in Alzheimer's disease (AD). However, at picomolar concentrations, the peptide is needed to ensure long-term potentiation (LTP) and memory. Here, we show that extracellular 200 pm oAbeta42 concentrations increase neurotransmitter release, number of docked vesicles, postsynaptic density length, and expression of plasticity-related proteins leading to the conversion of early LTP into late LTP and of short-term memory into long-term memory. These effects require alpha7 nicotinic acetylcholine receptors and are mediated through the nitric oxide/cGMP/protein kinase G pathway. The knowledge of Abeta function in the healthy brain might be useful to understand the causes leading to its increase and detrimental effect in AD. |
