Influence of amyloid‐beta isoforms in different in vitro models: Molecular and cell biology/neurodegeneration and neuroprotection

BackgroundAlzheimer disease (AD) is a complex multifactorial neurodegenerative disorder, characterized by mild cognitive impairment and late dementia. Understanding and treatment of AD is one of the greatest challenges in modern medicine. The pathological brain features includes formation of extracellular amyloid plaques, intracellular neurofibrillary tangles, leading to neuronal cell death. The underlying process, onset and progression are not yet elucidated, although impaired neurogenesis, synaptic dysfunction, and dysregulation of lipid metabolism are known to be involved. Homeostatic balance of Amyloid‐beta (Aβ) peptide during normal brain development and function, are depending on soluble or insoluble isoforms, aggregation state, developmental stage of the brain and concentration of Aβ peptide. Physiological and pathophysiological features of Aβ peptide remain controversial due to complexity, inconsistency and contradictory results. Investigating the effect of low concentration of human synthetic Aβ isoforms on adult neurogenesis, synaptic plasticity, and alteration of lipid metabolism might help better understanding the biochemical pathways in AD.MethodWe performed immunofluorescence, high performance thin layer chromatography, and mass spectrometry analyses on hippocampal neurons, glial cells and neurospheres treated with and without low concentration (1µM) of human synthetic Aβ40 and Aβ42 for 3‐12 hours.ResultPreliminary results of neurospheres treated with Aβ40 and Aβ42 showed altered levels in stem cell differentiation towards neuronal phenotype. The hippocampal neurons showed synaptic loss after 3‐12 hours. Lipid analysis showed altered levels of phospholipids (e.g. Phosphatidylcholine, Phosphatidylserine) and sphingolipids in hippocampal neurons after 3‐12 hours of Aβ40 and Aβ42 treatment compared to glial cells. Glial cells showed altering lipid levels after 3 hours of Aβ42 treatment and 12 hours for both Aβ40 and Aβ42 treatment.ConclusionPreliminary results showed that treatment with low concentration of Aβ40 and Aβ42 might have neurotrophic effect on stem cell differentiation and synaptic loss on hippocampal neurons. Lipid profiles showed altering levels in phospholipids and sphingolipids in both glial cells and hippocampal neurons. These results will have potential impact in a better understanding, finding of new biomarkers for diagnostics, and developing new therapeutics for AD.