The Neuroprotective AβCore Rescues Full Length Aβ42 – Linked Alterations in Dendritic Spine Structure , Synaptic Density, and Glutamate Receptor Expression
The Neuroprotective AβCore Rescues Full Length Aβ42 – Linked Alterations in Dendritic Spine Structure , Synaptic Density, and Glutamate Receptor Expression
Date
2024
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Shontell, Ruth Mariko
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Nichols, Robert A.
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Cell and Molecular Biology
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Alzheimer’s disease (AD) is the most common form of dementia and is currently the seventh leading cause of death in the United States. Although first described over a century ago, there are currently no cures. Histopathologically, AD is characterized by the presence of extracellular plaques composed primarily of beta-amyloid (Aβ) peptide in fibrillar form and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau organized in paired-helical filaments in regions and subregions of the brain involved in memory processes (episodic and working), attention, spatial orientation and navigation, language (word retrieval and syntax), and higher order reasoning. During AD pathogenesis, the most prominent neurodegenerative change is progressive dysfunction and eventual loss of synapses in these regions, correlated with the accumulation of soluble oligomeric Aβ, but not plaques, and the primary early symptom of compromised short-term memory. Later, there is profound loss of neurons. Across these phases, there is progressive neuroinflammation, which is, in turn, strongly connected with synapse and neuron loss. There is abundant evidence that pathological levels of Aβ can directly compromise synaptic function and then trigger damage leading to synapse death. However, the focus of research to date has primarily been on either decreased innervation due to loss of presynaptic terminals or altered postsynaptic dendritic spine structure, without a complete understanding of the relation between the two sides of the synapses. Here, I incorporated an approach to examine the impact of Aβ on both the presynaptic and postsynaptic elements, focusing, in particular, on the postsynaptic density, using a volumetric assessment via microscopic imaging.
As a means to prevent or reverse the impact of Aβ on synapse and neuronal cell death, our laboratory discovered a neuroprotective hexapeptide sequence within the neurotoxic full-length Aβ peptide. We showed that this neuroprotective hexapeptide, named the AβCore, can reverse Aβ-triggered deficits in synapse function, but have only preliminarily examined the prevention of Aβ-induced changes in synapse structure by the AβCore. Moreover, none of the studies on Aβ-linked changes in synaptic structure considered the potential impact of nerve – synapse activity, particularly on-going synaptic dynamics. The studies described here were thus based on the hypothesis that the AβCore protects against full length Aβ42 – linked alteration in synaptic structure. In relation to this working hypothesis, the studies were guided by two aims: Aim 1 - Determining the neuroprotective effects of the AβCore on synaptic structure: Dendritic Spines in relation to presynaptic association and Aim 2 - Determining the impact of the neuroprotective effect of the AβCore on synaptic structure in the context of synaptic plasticity induced by chemical long-term potentiation. As noted, the postsynaptic density (PSD) was a primary focus, as this essential synaptic structure is a critical postsynaptic organizer for excitatory synapse signaling and its size and functional composition change in direct relation to synaptic dynamics, growing with increased synaptic strength and shrinking with decreased synaptic strength.
I found that in mouse hippocampal neuron cultures Aβ induced a reduction in postsynaptic dendrite spine volume, consistent with previous findings for a reduction in cross-sectional spine size, and a corresponding reduction in PSD volume and surface area on the spines, without an acute change in PSDs/ spine. All changes were prevented by co-administration of the AβCore. There was a curious trend for the AβCore to increase the PSD counts across the spine population. On the presynaptic side, Aβ had no acute effect on the number or size of presynaptic terminals, while, intriguingly, the AβCore strongly increased the number and volume of the presynaptic terminals, speculated to reflect terminal sprouting. In the context of positive synaptic dynamics, mimicking long-term potentiation via application of select chemical reagents (cLTP) to ex vivo organotypic mouse hippocampal slice cultures, PSD volume was increased with cLTP, consistent with previous observations, and that was compromised by Aβ and prevented by the AβCore.
In conclusion, my findings indicate that the AβCore can prevent the Aβ-associated compromise of synaptic structure.
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114 pages
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