Elevated ganglioside GM2 activator (GM2A) in human brain tissue reduces neurite integrity and spontaneous neuronal activity

Abstract

Background Alzheimer’s Disease (AD) affects millions globally, but therapy development is lagging. New experimental systems that monitor neuronal functions in conditions approximating the AD brain may be beneficial for identifying new therapeutic strategies. Methods We expose cultured neurons to aqueous-soluble human brain extract from 43 individuals across a spectrum of AD pathology. Multi-electrode arrays (MEAs) and live-cell imaging were used to assess neuronal firing and neurite integrity (NI), respectively, following treatments of rat cortical neurons (MEA) and human iPSC-derived neurons (iN) with human brain extracts. Results We observe associations between spontaneous activity and Aβ42:40 levels, between neurite integrity and oligomeric Aβ, and between neurite integrity and tau levels present in the brain extracts. However, these associations with Aβ and tau do not fully account for the effects observed. Proteomic profiling of the brain extracts revealed additional candidates correlated with neuronal structure and activity. Neurotoxicity in MEA and NI assays was associated with proteins implicated in lysosomal storage disorders, while neuroprotection was associated with proteins of the WAVE regulatory complex controlling actin cytoskeleton dynamics. Elevated ganglioside GM2 activator (GM2A) associates with reductions in both NI and MEA activity, and cell-derived GM2A alone is sufficient to induce a loss of neurite integrity and a reduction in neuronal firing. Conclusions The techniques and data herein introduce a system for modeling neuronal vulnerability in response to factors in the human brain and provide insights into proteins potentially contributing to AD pathogenesis.

A network pharmacology and molecular docking investigation on the mechanisms of Shanyaotianhua decoction (STT) as a therapy for psoriasis

“…[ 37 ] GM2A is a lipid transfer protein that stimulates the enzymatic processing of gangliosides and activates T cells via lipid presentation while acting as a gene encoding lysosomal enzyme. [ 38 ] Katarzyna et al [ 39 , 40 ] demonstrated that GM2A was up-regulated in an in vitro psoriatic model established using Hacat cells. MMP12 (human macrophage metalloproteinase) has been identified as an elastolytic metalloproteinase secreted by inflammatory macrophages [ 41 ] ; the levels of MMP12 messenger RNA (mRNA) were 17-fold higher in psoriatic lesions than in NL skin.…”

Repopulated spinal cord microglia exhibit a unique transcriptome and contribute to pain resolution

“…Elevated levels of GM2A in culture reduce neurite extension and neuronal firing rate, which may be beneficial in the context of pain and dorsal horn circuitry. 71 …”

Methods for the isolation and analysis of Aβ from postmortem brain

“…To exclude artifacts arising due to postmortem delays and/or freeze-thawing of tissue, for certain studies it will be important to investigate the use of fresh biopsy tissue. Nonetheless, other investigators have already employed our experimental paradigms ( Sideris et al, 2021 ; Emin et al, 2022 ; Hsieh et al, 2022 ; Liu et al, 2022 ; Stern et al, 2022 ) and we expect that these protocols will be further exploited. For instance to examine the bioactivity of tau and α-synuclein ( Corbett et al, 2020 ).…”