Table 1 Main receptors and their implications in Aβ binding-mediated neurotoxic effects [103]
Receptor | Localization | Proposed mechanisms |
|---|---|---|
NMDAR | Postsynaptically located on dendrites and dendritic spines | Impairment of NMDAR activity: removal from the cell surface and triggering of synaptic depression signalling pathways Increase of NMDAR function: AβOs induce neuronal oxidative stress through an NMDAR-dependent mechanism AβOs bind to NMDAR →excessive activation of NMDAR →inflow of Ca2+ to neurons →excitotoxicity |
AMPAR | Hippocampal pyramidal neurons and dendritic spines | AβOs → synaptic dysfunction by inducing calcineurin-dependent internalization of AMPAR |
PrPC | Brain neurons and spinal cord | Initial interaction of AβOs with PrPC on the neuronal surface which leads to: Disturbed regulation of BACE1 activity Inhibition of elongation of Aβ fibrils Intracellular Ca2+ increase in neurons via the complex PrPC-mGluR5 →impairment of synaptic plasticity |
mGluR5 | Hypothalamus and cortex | Complexes of AβOs with PrPC generate mGluR5-mediated influx of Ca2+ in neurons → excitotoxicity AβO-PrPC-mGluR5 complexes signalling pathway involved in dendritic spine loss |
β2ARs | Locus coeruleus, hippocampus and cortex | AβOs induce the degradation of β2ARs, which leads to: Enhanced γ-secretase activity → Aβ plaque formation Reduction of neurogenesis Reduction of the levels of synapse-associated proteins such as synaptophysin, synapsin 1, and PSD-95 |
α7nAChR | Septo-hippocampal region and cortical neurons | Aβ42 binds to α7nAChR → loss of cholinergic neurons in the brain → receptor internalization and intracellular accumulation of Aβ |
IR | Choroid plexus, olfactory bulb and regions of the striatum and cerebral cortex | AβOs bind to neuronal IR → impaired insulin signalling and brain insulin resistance → elevated Aβ production and reduced AβO clearance → Aβ deposits in the brain → neuronal damage |
p75NTR | White matter brain regions and spinal cord | AβOs bind to membrane p75NTR → formation of annular amyloid pores and ion channels → induction of aberrant cytoskeletal changes in dendritic spines AβOs bind to IGF-1R → phosphorylation of IGF-1R → induced p75NTR expression → cell death by fibrillary form of Aβ |
ILR | Hippocampus and surface of B lymphocytes, dendritic cells, natural killer cells, macrophages, granulocytes, mast cells, etc | AβOs bind to PirB → impartment of synaptic plasticity → disruption of hippocampal long-term potentiation → Aβ-induced deficits of memory AβOs bind to FcγRIIb → AβO-induced inhibition of long-term potentiation → Aβ-mediated neuronal dysfunction |
TREM2 | Surface of immune cells of myeloid origin | AD-associated TREM2 mutations → reduction of AβOs binding and degradation of Aβ → microglial depolarization, induction of K+ current into cells as well as increased cytokine expression and secretion, cells migration, proliferation, apoptosis, and morphological changes of microglia |
Eph4A EphB2 | Hippocampal neurons | AβOs reduce Eph receptor expression, promote its endocytosis and its degradation in the proteasome, which leads to: Loss of dendritic spine Synaptic dysfunction Increase of synaptoneurosomes Impairment of NMDAR functioning and cognitive deficits |
RAGE | Blood–brain barrier | Expression of RAGE is increased in the AD brain → RAGE is responsible of Aβ influx from plasma to BBB → increase of free Aβ fraction in plasma |
LPR2 | Choroid plexus epithelium and ependymal cells covering the brain ventricles | Aβ alone did not bind directly to LRP-2, whereas complexes of Aβ-40 with ApoJ are able to react with LRP-2 → clearance of Aβ |
VDR | Broadly expressed in all brain regions | 1,25-(OH)2D3 binds to VDR → increase the expression of amyloid transporters (i.e. LRP-1) → increase of transport of Aβ across the BBB → Aβ clearance |
SIRT1 | Predominantly located in the nucleus, but also in the cytosol of neurons of the hippocampus and hypothalamus | SIRT1 deficiency has been described to be responsible for the increased risk of insulin resistance, obesity and diabetes, which in turn are risk factors of AD SIRT1 deficiency has been described to be involve in the reduction of normal cognitive function and synaptic plasticity Reduction of SIRT1 → reduction of α-secretase activity → enhancement of amyloidogenic processing of APP |