Depressive symptoms score and risk of incident spinal pain in middle-aged and elderly populations: a prospective cohort study based on china health and retirement longitudinal study data.

The amyloid precursor protein (APP) is a type I transmembrane protein expressed in the brain as well as other organs (). APP was discovered in 1987 during a search to uncover the source of the amyloid beta peptide (Aβ) (; ; ), the main component of the amyloid plaques associated with Alzheimer’s disease (AD) (). APP undergoes proteolytic processing to release not only Aβ but also other fragments which have important roles in the brain. APP can be cleaved by either α- or β- secretase followed by γ-secretase. α-secretase cleaves within the Aβ region and thus precludes Aβ generation and produces soluble APP α (sAPPα), P3, and the APP intracellular domain (AICD). β-secretase initiates the amyloidogenic pathway which generates sAPPβ, Aβ, and AICD (). APP can also be cleaved by η-secretase prior to α or β cleavage within the sAPP region to generate sAPPη and additional fragments Aη-α or Aη-β (). Full-length APP and its fragments are involved in crucial brain functions (). They modulate neurodevelopmental processes such as axonal outgrowth, dendritic arborization, neurogenesis, and neuronal migration (; ). In mature neurons, full-length APP and sAPPα regulate synaptic structure, plasticity, and neurotransmission (; ). Though best known for its neuronal roles, APP is also implicated in glial and endothelial functions(). APP knockout (KO) mice display hypomyelinated axons (), blunted microglial and astrocytic inflammatory responses (), mitochondrial fragmentation in astrocytes (), and reduced production of endothelial nitric oxide species (). In human stem cell-derived microglia, APP knockdown impaired the function of voltage-gated proton channels implicated in microglial activation (). Despite these observations, the role of APP in glial cells remains largely undefined and understudied. Identifying proteins that interact with APP and its fragments has been a key strategy to elucidate its physiological functions (). In 2019, full-length APP () and its secreted ectodomain sAPPα () were shown to interact with the γ-amino butyric acid (GABA) type B receptor (GABAR). GABAR is a class C G-protein coupled receptor (GPCR) and is an obligatory heterodimer (). The GABAR1 subunit contains the endogenous agonist binding site, and GABAR2 is intracellularly linked to G-proteins. The GABAR1 subunit has various isoforms with R1a and R1b being the main two variants responsible for GABAR diversity in humans (). The main difference between the two isoforms is the presence of two sushi domains on the N-terminus of R1a but not in R1b due to differential promoter usage (). These sushi domains are responsible for the preferential localization of the GABAR1a subunit to axon terminals (; ). The intact (full-length APP) () and shed (sAPPα) ectodomain () both bind at the N-terminal sushi domain 1 of GABAR1a (). The sAPP-GABAR interaction was shown to reduce synaptic vesicle release consequently modulating hippocampal synaptic plasticity and neurotransmission () as well as neurite outgrowth (). Moreover, deletion of APP impaired GABAR-mediated presynaptic inhibition and axonal GABAR levels (). The downstream mechanism mediating the effects of sAPPα-GABAR signaling remains under investigation as studies suggest it may deviate from canonical GABAR signaling (). In the brain, both GABAR1a and GABAR1b are expressed in most neuronal subpopulations including glutamatergic, dopaminergic, and GABAergic neurons (). Neurons utilize canonical GABAR signaling pathways to regulate key processes like synaptic transmission and excitatory/inhibitory balance (). GABARs couple to Gα and Gβγ proteins to inhibit adenylyl cyclase and presynaptic Ca2+ channels to reduce presynaptic release probability and activate postsynaptic GIRK channels to reduce neuronal excitability (; ; ).The inhibitory functions of GABAR have been extensively studied in neurons but are not as well characterized in glial cells. Oligodendrocytes express functional GABAR1 that can modulate adenylyl cyclase signaling (). Furthermore, GABAR activation using Baclofen, an agonist with no isoform selectivity, regulates oligodendrocyte precursor cell differentiation in vitro () and can accelerate remyelination after induced primary demyelination in mouse spinal cord (). Studies in astrocytes and microglia show that these glial cells also express GABAR1 and its activation using baclofen resulted in a decreased inflammatory response to lipopolysaccharide (LPS) (; ; ). A study using Baclofen in endothelial cells suggests that they also express functional GABARs which can modulate their response to homocysteine toxicity (). Although some of these studies detected both isoforms of GABAR1, it remains unclear whether glial cells exhibit preferential expression of a specific isoform.