Deciphering apolipoprotein e-associated alterations in alzheimer¿s disease

• Autores: Matthew Paul Lennol
• Directores de la Tesis: Javier Saez Valero (dir. tes.), Inmaculada Cuchillo Ibañez (codir. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2023
• Idioma: español
• Tribunal Calificador de la Tesis: Jordi Perez Tur (presid.), Maria Salud Garcia Ayllon (secret.), Francisco Rafael López Picón (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Miguel Hernández de Elche
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• Resumen

  • Alzheimer's disease (AD) is an age-related neurodegenerative disorder and the main cause of dementia, characterised by two specific pathological hallmarks: the extracellular deposition of neurotoxic amyloid beta peptides in the form of senile plaques, and the intracellular accumulation of hyperphosphorylated forms of the cytoskeletal protein tau in neurofibrillary tangles. Two forms of AD exist, early-onset AD, which occurs before the age of 65 years and is usually hereditary; and late-onset, or sporadic AD (sAD), which accounts for more than 95% of cases and is linked to a series of genetic and environmental risk factors. APOE, the gene encoding the apolipoprotein E (apoE) protein, is the most prominent genetic risk factor for sAD. Three allelic variants exist in humans: APOE ¿2, the least common variant linked to a reduced risk of developing AD; APOE ¿3, the most common variant considered to be risk-neutral; and APOE ¿4, linked to an increased risk of AD. The isoforms encoded by the allelic variants differ in single amino acid substitutions at positions 112 or 158; with apoE4 presenting Arginine at both positions, thus being unable to form disulphide-linked dimers, the most effective form of apoE to interact with cellular receptors. ApoE is the most important cholesterol transporter in the brain, however it has many other functions, some of which are dependent on its interactions with receptors, including apoER2, the main ligand of which is reelin. Reelin is a large glycoprotein that regulates neuronal migration during brain development, and is implicated in synaptic transmission, plasticity, and memory in the adult brain.

    In this doctoral thesis, we aimed to characterise altered patterns of apoE and reelin proteins in the cerebrospinal fluid (CSF) of AD patients, and to describe a relatively unknown apoE receptor, LRP3, and determine how it interacts with key proteins in AD. An imbalance of apoE glycoforms, with an increased abundance of immatures species, was detected in AD samples compared to controls, alongside the appearance, exclusively in AD samples, of an aberrant high molecular mass species that was compatible with dimers but resistant to reducing agents. ApoE4 also participates in these aberrant dimers, despite the inability of these isoforms to form disulphide-linked dimers. The apoE glycoform imbalance was replicated in AD brain samples. Full-length reelin levels decreased in AD CSF and presented a different profile of fragments, characterized by increased C-terminal region cleavage and decreased N-terminal region cleavage, as compared with control subjects. Once again, aberrant complexes of high molecular mass, composed mainly of N-terminal reelin fragments, were also detected in AD, regardless of the APOE genotype. Regarding LRP3, we found a reduced presence of the receptor in the brain of AD patients and discovered that the expression of LRP3 is modulated by apoER2; and that LRP3 can in turn influence APP and Aß levels. These results indicate a possible pathological situation in which modifications of the apoE and reelin proteins affect their protective functions and the efficiency of apoER2 signalling, thus contributing to the exacerbation of AD. These modifications can also affect mechanisms of co-regulation of AD key proteins, such as APP, thus implicating the LRP3 receptor. The apoE glycoform imbalance and the fragmentation profile of reelin, alongside the appearance of aberrant aggregates of both proteins, could serve as potential read-outs of impaired signalling, and may also have potential for AD diagnosis and progression.