Unbalanced Regulation of α7 nAChRs by Ly6h and NACHO Contributes to Neurotoxicity in Alzheimer's Disease

Abstract

α7 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the brain where they promote fast cholinergic synaptic transmission and serve important neuromodulatory functions. However, their high permeability to Ca2+also predisposes them to contribute to disease states. Here, using transfected HEK-tsa cells and primary cultured hippocampal neurons from male and female rats, we demonstrate that two proteins called Ly6h and NACHO compete for access to α7 subunits, operating together but in opposition to maintain α7 assembly and activity within a narrow range that is optimal for neuronal function and viability. Using mixed gender human temporal cortex and cultured hippocampal neurons from rats we further show that this balance is perturbed during Alzheimer's disease (AD) because of amyloid β (Aβ)-driven reduction in Ly6h, with severe reduction leading to increased phosphorylated tau and α7-mediated neurotoxicity. Ly6h release into human CSF is also correlated with AD severity. Thus, Ly6h links cholinergic signaling, Aβ and phosphorylated tau and may serve as a novel marker for AD progression.SIGNIFICANCE STATEMENTOne of the earliest and most persistent hypotheses regarding Alzheimer's disease (AD) attributes cognitive impairment to loss of cholinergic signaling. More recently, interest has focused on crucial roles for amyloid β (Aβ) and phosphorylated tau in Alzheimer's pathogenesis. Here, we demonstrate that these elements are linked by Ly6h and its counterpart, NACHO, functioning in opposition to maintain assembly of nicotinic acetylcholine receptors (nAChRs) within the physiological range. Our data suggests that Aβ shifts the balance away from Ly6h and toward NACHO, resulting in increased assembly of Ca2+-permeable nAChRs and thus a conversion of basal cholinergic to neurotoxic signaling.

Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly

“…Homomeric α7 nAChRs are the nicotinic receptors with the highest calcium permeability [ 168 , 169 , 170 ], and too much calcium influx leads to cell injury or death [ 171 ]. Recently, Wu et al [ 172 ] showed that Ly6h antagonizes the effects of NACHO on α7 nAChR assembly in both neurons and HEKtsa cells. Ly6h is a member of the prototoxin Ly6/uPAR protein family [ 173 ] that all have three-finger folding structures similar to snake a-neurotoxins such as a-bungarotoxin [ 25 ].…”

Neuroimmune Regulation in Sepsis-Associated Encephalopathy: The Interaction Between the Brain and Peripheral Immunity

“…In the CNS, α7 nAChR is located on the surface of various nerve cells including astrocytes, microglia cells, interneurons, and immature granule cells, which are distributed in the basal ganglia, the hippocampus, and the brain gray matter (140)(141)(142). It is believed that α7 nAChR can be involved in many psychiatric and neurological disorders including neuroinflammation, Parkinson's disease, and Alzheimer's disease by regulating neurotransmitter release, synaptic plasticity, and signal transduction (143)(144)(145). The functions of α7nAChR in the nervous system are determined by location, time, and context.…”

“…With the development of the genome-wide association study, a series of studies confirmed that the CHRNA7 genes encoded for the α7 nAChRs in the human brain and the variations within CHRNA7 were associated with the abnormal response of CAP ( 140 , 152 ). In addition, chaperone proteins such as resistance to inhibitors of cholinesterase-3 (RIC3) Ly6h and NACHO could greatly affect the expression and function of nAChRs ( 143 , 153 , 154 ).…”

Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease

“…The endogenous proteins from the Ly6/uPAR family (Lynx1, Lynx2, Lypd6, Lypd6b, Ly6e, Ly6h, Ly6g6e, PSCA, SLURP-1, SLURP-2) modulate nAChR's function [15][16][17][18][19][20][21][22][23][24][25]. Expression of Lynx1, an α7-nAChR positive modulator in the brain [17,26], is down-regulated in the frontal cortex of 3xTg-AD mice with β-amyloid and tau pathology [27].…”