Dear Rajsekhar Roy

The following review papers may be useful:

Article Amyloid Beta-Related Alterations to Glutamate Signaling Dyna...

https://www.frontiersin.org/articles/10.3389/fnins.2019.00043/full

Good Luck

Hi Rajsekhar Roy,

In brief, Abeta oligomers could bind on the NMDA receptor allowing for a dysregulation influx of Ca2+ causing cytotoxicity.

Thanks,

Benson

The short answer is we don't know. The long answer (just some options- none of these are mutually exclusive). It could be...

1) An overall increase in glutamate (as mentioned by Bazzari), and the NMDA receptor goes along for the ride as soon as the membrane gets depolarized enough to relieve the Mg2+ block. But mechanistically, what drives the increased glutamate early in the disease process is not clear.

2) A specific receptor driven process (as mentioned by Peng). Prior work shows that NMDA receptors do play a role, but it is not clear that NMDARs are direct molecular targets. There are a fair number of molecules that are in that same boat. A couple that have a little more research behind them as candidates for the as yet undefined "ABO toxin receptor" (pros and cons to each)

• PrPc (cellular prion protein) hypothesis (binding site might be on lipid rafts, might be the Sigma opioid receptor)
• NaKATPase alpha 3
• The receptor hypothesis is compelling because the responses measured appear to obey the rules of receptor pharmacology, with selectivity, specificity and saturability. Antagonists can block the response but keep in mind that those antagonists work by action on the ligand, rather than the conventional competitive antagonists that would compete for binding at the receptor (partly because we don't know what that receptor is- one idea is that whatever it is exists on lipid rafts).
• Note- there is an fascinating new article by Tanzi's group exploring the concept that APP-> AB may be made in mitochondrial endoplasmic lipid rafts that are in close contact with mitochondria

• Article Axonal generation of amyloid-β from palmitoylated APP in mit...

3) ABOs can insert themselves in cell membranes, and can form ion-conducting pores there. If ABO formation is localized to synapses, this would cause synapse specific disruption- the pore forming event itself may not be classically receptor pharmacology, but the response of the synapse to this insult may itself be saturable.

• This, and other synapse-localized insults, may lead to localized tau depolymerization, the fragments of which can then act as nucleation sites for the molecular machinery involved in the 'translational stress response', and might represent one way that the baton is passed from Abeta to Tau in AD

• Article Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA...

4) what does APP normally do?- the focus on Abeta Oligomers (ABOs) has sort of shifted the focus away from what 'normal' amyloid precursor protein (APP) does, and what the consequences of its relative loss as ABO rises, might be. This is reviewed here

https://www.nature.com/articles/nrn.2017.29

and is probably worth keeping in mind while investigating ABOs. For example, a long time ago (1996) we showed that APPs promote K+ channel activity, and proposed that APPs may act as a retrograde neurotransmitters that feedback inhibit the presynapse, reducing firing. So the loss of this APP function, in addition to whatever ABOs are doing, may be relevant (normal function of APP in the context of brain tissue would be worth investigating).

I cribbed some of this info from the following review

Article The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

https://www.sciencedirect.com/science/article/abs/pii/S0014488607003913

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Amyloid beta peptides and glutamatergic synaptic dysregulation‏

Thank you all for sharing your insights on the topic.

Also to mention I have found one study describing the role of amyloid oligomers in synaptic plasticiy and its effect on synaptic and extrasynaptic receptors, which I guess brings the connection to the whole story. Nevertheless, more study is required to come to any conclusion.

https://www.jneurosci.org/content/39/30/5986.long