Identification of plasma biomarkers for the early Alzheimer Disease diagnosis through lipid peroxidation and multi-omics studies
Doctorando: María del Carmen Peña Bautista
Dirigida por: Dra. Consuelo Cháfer Pericás y el Dr. Máximo Vento Torres
Grupo de investigación en Enfermedad de Alzheimer (GINEA)
This PhD thesis is focused on the identification and determination of reliable and minimally invasive biomarkers for Alzheimer Disease (AD) diagnosis in its early stages, as well as to advance in the knowledge of the pathophysiological mechanisms involved in the course of the disease.
AD is the most common cause of dementia and it generates a great social and economic impact. However, the lack of early accessible diagnosis biomarkers hinders the initiation of treatments and limits research into new therapies to cure or slow down the course of the disease. AD is a complex disease with multiple pathological pathways such as protein accumulation (amyloid β42 (Aβ42, hyperphosphorylated Tau (p-Tau)), but also pathophysiological pathways such as oxidative stress (OS), lipid dysregulation, dysregulation of the clearance machinery, etc. Therefore, this PhD thesis is divided into two parts, the first one dedicated to the studies of lipid peroxidation compounds as biomarkers of the disease and the second part dedicated to the omics studies (metabolomic, lipidomic, epigenomic) in patients with early AD to examine the pathways involved in early AD and to provide new potential diagnosis biomarkers.
Regarding lipid peroxidation-derived compounds, they were measured in urine and plasma samples by a validated method on based ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). The developed diagnosis models showed discriminatory capacity between early AD and controls, especially for plasma samples. In addition, these compounds were able to discriminate controls from preclinical AD cases and AD from other dementias.
In addition, omic analyses (metabolomics, lipidomics, epigenomics) were carried out in plasma samples from AD and non-AD cases. These analyses revealed the dysregulation of some metabolites (choline, rescinamine, soraphen A, Lyso PE(20:0/0:0), Lyso PE(0:0/20:0), lipids (LysoPC (18:0), LysoPE (0:0/22:1 (13Z)), cardiolipins, phosphocholine, 1-O-Palmitoil-2-O-acetil-sn-glycero-3-phosphorilcholine, 18:1 LPE, 18:0 LPC, 16:1 SM, 16:0 SM) and miRNAs (hsa-miR-92a-3p, hsa-miR-486-5p, hsa-miR-29a-3p). In fact, these miRNAs could be involved in fatty acids metabolism.
The complete characterization of plasma biomarkers from AD patients with special attention on OS and lipid metabolism could help to obtain an early diagnosis and to define the metabolic pathways altered in each individual allowing an early and personalized treatmentImport Outlook Calendar Import Google Calendar