Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory

Abstract

Failure of anti-amyloid-␤ peptide (A␤) 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 A␤ 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 A␤ 42 (oA␤ 42) on synaptic glutamatergic function in male and female mice. We found that 200 pM oA␤ 42 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. oA␤ 42 also produced postsynaptic changes as shown by an increased length of postsynaptic density, accompanied by an increased expression of plasticity-related proteins such as cAMPresponsive element binding protein phosphorylated at Ser133, calcium-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for A␤ 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 oA␤ 42. These effects were present upon extracellular but not intracellular application of the peptide and involved ␣7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oA␤ 42 in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high A␤ levels in the AD brains.

Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer’s disease neuropathology and atypical effects of the cholinergic antagonist atropine

“…One of the problems in relating these papers to the results presented here is that it is hard to equate superfusion of synthetic peptides to endogenous production of Aβ from mutated APP. Nevertheless, the published data using exogenous application of Aβ peptides are consistent with what we have shown, because diverse changes in synaptic activity have been documented, both increases and decreases (Gulisano et al, 2019; Kelly et al, 1996; Parameshwaran et al, 2007; Ripoli et al, 2014; Yao et al, 2013).…”

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

“…4). Whilst low levels of Aβ can increase dendritic spine density [194], increase the number of docked vesicles [92], enhance glutamate release, promote excitotoxicity, and disrupt calcium homeostasis (particularly in early stages of disease) [7,35,225], Aβ production after synaptic activity could also act via negative feedback to prevent hyperactivity [123]. Indeed, Aβ can induce spine collapse and synapse loss [231,274], increase the proportion of silent neurons [35], and disrupt neurotransmitter release via depletion of presynaptic PIP 2 [99] .…”

Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

“…The Slutsky lab elegantly demonstrated that increasing Aβ by neprilysin inhibition increases SV recycling, while decreasing physiological Aβ levels by anti-Aβ antibody-promoted degradation, in contrast, decreases SV recycling (Abramov et al, 2009). More recent data indicate that exogenous picomolar preparations of oligomeric Aβ42 can augment neurotransmitter release and the length of the postsynaptic density, resulting in a late-LTP (Gulisano et al, 2019). The mechanisms of how endogenous Aβ regulates synaptic vesicle recycling and PSD recruitment for modulating synaptic transmission and plasticity are unclear.…”

“…The mechanisms of how endogenous Aβ regulates synaptic vesicle recycling and PSD recruitment for modulating synaptic transmission and plasticity are unclear. Some evidence indicates that Aβ can bind to alpha7nicotinic acetylcholine receptors (Puzzo et al, 2008;Gulisano et al, 2019) to induce presynaptic calcium entry. Overall, the evidence points to an Aβ physiological role, but it is still not clear which form of Aβ is relevant.…”