@The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease (Rudy et al)

2022-05-20: reference:

[@The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease (Rudy et al)] #

• The best correlate of memory deficits in Alzheimer’s patients, however, is not Aβ plaque burden or neurofibrillary tangles, but synapse loss.
• Excitotoxicity occurs when uncontrolled glutamate release surpasses the capacity of astrocytic clearance mechanisms (EAAT1 and -2), leading to an overabundance of extracellular glutamate and excessive activation of eNMDAR. Basically, Aβ accumulation may initially only activate sNMDAR, but eventually spillover (from sNMDAR or astrocytes) andor inhibition of reuptake activates eNMDAR and the synapse shifts towards LTD.
• Cell death is also due to excess intracellular calcium. I don’t know why this couldn’t happen through pure sNMDAR.
• the localized release and astrocytic uptake of these coagonists has also been hypothesized to explain the differences in co-agonist use by S-NMDARs vs. eNMDAR.
• The pathways triggered by eNMDARs are not directly related to calcium overload; even after triggering equivalent calcium concentrations… indeed @Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways (2002) explains they have opposite effects on CREB. How? Don’t know. Maybe proximity to the nucleus.

• ERK is also bidirectionally modulated on/off by s/eNMDAR.
• eNMDAR activates FOXO, while sNMDAR suppresses it. Increases Caspase 3.
• eNMDAR activates Calpain-mediated STEP cleavage, while sNMDAR has no effect.
  • This is simply by means of calcium influx of course, so I guess they must be colocalized.
  • STEP down-> Fyn up-> Increase in the surface expression of NR2B. The question is how much promotes eNMDAR exocytosis?
• Increased activation of NR2B-containing receptors induces Tau phosphorylation, while blockade of NR2B receptors prevents this phosphorylation. Likewise, blockade of extrasynaptic NR2B receptors abolishes tau-mediated cytotoxicity in a cell culture system.
• 450
  • Tau transports Fyn to the spine. Naturally, excessive tau -> excessive fyn -> excessive eNMDAR stabilization.
  • Tau knockout mice were shown to be resistant to Amyloid β exposure!
    • I don’t think this means 100% or anything, though. Unless?:
      • *Blockade of NR2B receptors, or removal of tau, prevents Aβ-induced neuronal death *
      • Aβ-induced dendritic spine loss occurs via a pathway involving NR2A containing NMDARs and is tau-independent
    • Tau reductions, or expression of tau fragments that cannot transport Fyn to dendritic spines, prevent the memory deficits and network excitability caused by Aβ
  • Tau phosphorylation results in AMPAR endocytosis and a decrease in expression.
  • NMDA receptor activation increases tau phosphorylation of tau, at GSK-3β-dependent sites – PHF-1, AT8, and AT180 – leading to a decrease in Tau’s affinity for PSD-95 and an increase in tau’s interaction with Fyn.
    • Thus, stabilization of the PSD-95-Fyn-Tau-NR2B comlplex has a self-feedback loop (which facilitates LTD), until I assume you have to wait for STEP which is part of the typical eNMDAR cascade.
    • NMDA receptor-dependent phosphorylation of Tau is transient, whereas tau phosphorylation after 5 days of Amyloid β exposure is not.
• Aβ-induced astrocytic glutamate release increases E-NMDAR currents and decreases S-NMDAR currents, leading to synapse loss ??
  • My best guess is since astrocytes are more colocalized to eNMDAR, than presynaptic vesicles, they induce sNMDAR LTD, while astrocyte-eNMDAR maintains synaptic weight
• Aβ-induced mGluR5 (mechanistically coupled to NMDAR) potentially mediates excessive Ca2+ permeability. Inhibition of mGluR5 activity prevents the block of LTP induced by Aβ and is neuroprotective against Aβ.
  • And fwiw: Group I/II mGluR antagonist, LY341495 (10μM), enhances Aβ-mediated LTD, whereas application of an NMDAR antagonist, D-AP5 (50 μM), has no effect
• Astrocytes express Aβ-degrading proteases, including neprilysin (as one would deduce, it reduces p38 phosphorylation) and Insulin Degrading Enzyme.