Age-Related Transcriptional Deregulation of Genes Coding Synaptic Proteins in Alzheimer's Disease Murine Model: Potential Neuroprotective Effect of Fingolimod

• Published in: Frontiers in molecular neuroscience 2021-07, Vol.14, p.660104
• Main Authors: Jęśko, Henryk, Wieczorek, Iga, Wencel, Przemysław Leonard, Gąssowska-Dobrowolska, Magdalena, Lukiw, Walter J, Strosznajder, Robert Piotr
• Format: Article
• Language: English
• Subjects: Age; aging; Alzheimer's disease; Amyloid precursor protein; amyloid β; Animal cognition; Animal models; Brain research; Coding; Cortex; FTY720; FTY720/fingolimod; Gene expression; Gene regulation; Hippocampus; Laboratory animals; Lipid metabolism; Molecular Neuroscience; Mutation; Neurodegeneration; Neurodegenerative diseases; Neuromodulation; Neuroprotection; Neurosciences; Neurotoxicity; Phenotypes; Proteins; SNAP-25 protein; sphingolipids; Sphingosine 1-phosphate; Spinal cord; Synapsin; Synaptophysin; Synaptotagmin; Syntaxin; Transcription; Transcription factors
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2021.660104

Alzheimer's disease (AD) induces time-dependent changes in sphingolipid metabolism, which may affect transcription regulation and neuronal phenotype. We, therefore, analyzed the influence of age, amyloid β precursor protein (AβPP), and the clinically approved, bioavailable sphingosine-1-phosphate receptor modulator fingolimod (FTY720) on the expression of synaptic proteins. RNA was isolated, reverse-transcribed, and subjected to real-time PCR. Expression of mutant (V717I) AβPP led to few changes at 3 months of age but reduced multiple mRNA coding for synaptic proteins in a 12-month-old mouse brain. Complexin 1 ( ), SNAP25 ( ), syntaxin 1A ( ), neurexin 1 ( ), neurofilament light ( ), and synaptotagmin 1 ( ) in the hippocampus, and VAMP1 ( ) and neurexin 1 ( ) in the cortex were all significantly reduced in 12-month-old mice. Post mortem AD samples from the human hippocampus and cortex displayed lower expression of VAMP, synapsin, neurofilament light (NF-L) and synaptophysin. The potentially neuroprotective FTY720 reversed most AβPP-induced changes in gene expression ( , and ) in the 12-month-old hippocampus, which is thought to be most sensitive to early neurotoxic insults, but it only restored in the cortex and had no influence in 3-month-old brains. Further study may reveal the potential usefulness of FTY720 in the modulation of deregulated neuronal phenotype in AD brains.