Luke Mascarenhas

Introduction Lewy body dementia (LBD) is characterized by the accumulation of Lewy bodies or aggregates of misfolded, overexpressed α-synuclein (α-syn) in neurons or surrounding glial cells, leading to neuronal cell death^1,3. Previous studies demonstrated that α-syn and misfolded amyloid-beta protein (Aβ) play a role in the pathogenesis of dementia through Aβ-driven oligomerization and toxic conversion of α-syn¹. One study showed that treatment with Aβ caused a significant increase in mammalian target of rapamycin (mTOR) phosphorylation, a hallmark of autophagy, possibly affecting α-syn clearance².  Another study highlighted the metabotropic glutamate receptor 5 (mGluR5) as a potential mediator of the neurotoxic effects of Aβ and α-syn¹. These findings suggest possible important targets for therapeutic intervention in LBD patients. Methods Lin et. al obtained human neuroblastoma SK-N-MC cells and exposed the samples to varying dilutions of Aβ solutions. They observed changes in cell nucleus morphology, which is characteristic of apoptosis, using a microscope to view cells grown on a cover slip fixed in 4% paraformaldehyde after 24 h of treatment². Overk et al. generated α-syn/APP double transgenic mice to understand the role of α-syn and Aβ in mediating neurodegeneration in the hippocampus via mGluR5¹.  Results Lin et al. utilized immunofluorescence assays to demonstrate that Aβ significantly increases the number of α-syn aggregates in α-syn-overexpressed cells compared to non-Aβ treated groups, aka mock-transduced². Aβ markedly increases the number of apoptotic cells with fragmented nuclei in α-syn-overexpressed cells. Apoptosis is determined by fragmented nucleus morphology using DAPI fluorescence². Overk et al. found that endogenous α-syn was observed in a punctate pattern in the hippocampal regions of CA1 and CA3 in the control and Aβ only model; however, levels were significantly enhanced in the α-syn and α-syn/Aβ models¹.  Based on a previous finding that α-syn/Aβ resulted in approximately three-fold increase in intracellular calcium, Overk et al. found that α-syn expressing neuronal cell lines, Aβ oligomers promote increased intracellular Ca2+ levels, calpain I induction, and truncation of α-syn, leading to caspase-3-dependent cell death¹. Conclusions While both studies are not definitive and further research is needed into their explicit mechanisms, Aβ was seen in both studies to exacerbate α-syn aggregates. Aβ expressed in α-syn-overexpressed cells induced caspase 3 cleavage or apoptosis of neuronal cells. There are still no disease-modifying drugs for LBD, limiting current treatment to symptomatic relief and palliative care⁴. mGLUR5 receptors may be an important target for therapeutic intervention in LBD via mGLUR5 antagonists¹.

1. Overk CR, Cartier A, Shaked G, et al. Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5–implications for dementia with Lewy bodies. Mol Neurodegener. 2014;9:18.
2. Lin CL, Cheng YS, Li HH, et al. Amyloid-β suppresses AMP-activated protein kinase (AMPK) signaling and contributes to α-synuclein-induced cytotoxicity. Exp Neurol. 2016;275 Pt 1:84-98.
3. Sanford AM. Lewy Body Dementia. Clin Geriatr Med. 2018;34(4):603-615.
4. Outeiro TF, Koss DJ, Erskine D, et al. Dementia with Lewy bodies: an update and outlook. Mol Neurodegener. 2019;14(1):5.