A growing body of evidence indicates that pathological forms of amyloid beta (Aβ) peptide contribute to neuronal degeneration and synaptic loss in Alzheimer’s disease (AD). In this study, we investigated the impact of exogenous Aβ1-42 oligomers (AβO) and endogenously liberated Aβ peptides on transcription of genes for anti-oxidative and mitochondria-related proteins in cell lines (neuronal SH-SY5Y and microglial BV2) and in brain cortex of transgenic AD (Tg-AD) mice, respectively. Our results demonstrated significant AβO-evoked changes in transcription of genes in SH-SY5Y cells, where AβO enhanced expression of Sod1, Cat, mt-Nd1, Bcl2, and attenuated Sirt5, Sod2 and Sdha. In BV2 line, AβO increased the level of mRNA for Sod2, Dnm1l, Bcl2, and decreased for Gpx4, Sirt1, Sirt3, mt-Nd1, Sdha and Mfn2. Then, AβO enhanced free radicals level and impaired mitochondrial membrane potential only in SH-SY5Y cells, but reduced viability of both cell types. Inhibitor of poly(ADP-ribose)polymerase-1 and activator of sirtuin-1 more efficiently enhanced viability of SH-SY5Y than BV2 affected by AβO. Analysis of brain cortex of Tg-AD mice confirmed significant downregulation of Sirt1, Mfn1 and mt-Nd1 and upregulation of Dnm1l. In human AD brain, changes of microRNA pattern (miRNA-9, miRNA-34a, miRNA-146a and miRNA-155) seem to be responsible for decrease in Sirt1 expression. Overall, our results demonstrated a diverse response of neuronal and microglial cells to AβO toxicity. Alterations of genes encoding Sirt1, Mfn1 and Drp1 in an experimental model of AD suggest that modulation of mitochondria dynamics and Sirt1, including miRNA strategy, may be crucial for improvement of AD therapy.

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

Migraine is a common neurological disease that affects both women and men in a different age. It is believed that migraine is a multifactorial disease with strong genetic and environmental factors. Current molecular studies in migraine are focused on biochemical (homocysteine, asymmetric dimethylarginine) and genetic (ACE, MTHFR, MTR, MTRR, CBS, eNOS, NOTCH3) risk factors associated with vascular diseases. Polymorphisms and mutations in mentioned genes predispose to migraine as well as cardiovascular diseases and stroke. According to the literature data, 13-15% of migraine with aura patients suffer from vascular diseases, too. The strict relation between migraine with aura and stroke is observed in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lifestyle plays an important role both in the pathomechanism of migraine and vascular diseases. Hypertension, obesity, dyslipidemia, and diabetes mellitus are the important risk factors for those pathological conditions. Therefore, early diagnosis of migraine and the implementing effective pharmacotherapy can lead to the prevention of cardiovascular and cerebrovascular diseases.