AUTHOR=Jęśko Henryk , Wieczorek Iga , Wencel Przemysław Leonard , Gąssowska-Dobrowolska Magdalena , Lukiw Walter J. , Strosznajder Robert Piotr 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=14

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2021.660104

DOI=10.3389/fnmol.2021.660104

ISSN=1662-5099

ABSTRACT=<p>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 (<italic>Cplx1</italic>), SNAP25 (<italic>Snap25</italic>), syntaxin 1A (<italic>Stx1a</italic>), neurexin 1 (<italic>Nrxn1</italic>), neurofilament light (<italic>Nefl</italic>), and synaptotagmin 1 (<italic>Syt1</italic>) in the hippocampus, and VAMP1 (<italic>Vamp1</italic>) and neurexin 1 (<italic>Nrxn1</italic>) 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 (<italic>Cplx1, Stx1a, Snap25</italic>, and <italic>Nrxn1</italic>) in the 12-month-old hippocampus, which is thought to be most sensitive to early neurotoxic insults, but it only restored <italic>Vamp1</italic> 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.</p>