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Table 1 Main receptors and their implications in Aβ binding-mediated neurotoxic effects [103]

From: Nanomedicine-based technologies and novel biomarkers for the diagnosis and treatment of Alzheimer’s disease: from current to future challenges

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
  1. AβOs, amyloid-β oligopeptides; α7nAChR, Acetylcholine Receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; β2ARs, β2-Adrenergic Receptors; LPR2, lipoprotein-related protein 2; mGluR5, Metabotropic Glutamate Receptor 5; EphA4, EphB2, Tyrosine Kinase Ephrin Receptors; FcγRIIb, Fragment crystallizable gamma receptor II b; IGF-1R, insulin-like growth factor 1 receptor; ILR, Immunoglobulin-Like Receptors; IR, Insulin Receptor; NMDAR, N-methyl-D-aspartate receptor; p75NTR, p75 Neurotrophin Receptor; PirB, paired immunoglobulin-like receptor B: PrPC, Cellular Prion Protein; RAGE, Receptor for Advanced Glycation Endproducts; SIRT 1, Sirtuin 1; TREM2, Triggering Receptor Expressed on Myeloid Cells 2; VDR, vitamin D receptor