Thèse Rôle des Tanycytes dans la Physiopathologie de la Maladie d'Alzheimer H/F - 59

Établissement : Université de Lille
École doctorale : Biologie Santé de Lille
Laboratoire de recherche : Lille Neurosciences & Cognition
Direction de la thèse : Vincent PREVOT ORCID 0000000171853615
Début de la thèse : 2026-10-01
Date limite de candidature : 2026-04-28T23:59:59

Alzheimer's disease (AD) is driven in part by impaired clearance of amyloid- and tau, contributing to neuronal damage. Cerebrospinal fluid (CSF) biomarkers aid diagnosis, and the disease spectrum ranges from mild cognitive impairment (MCI) to advanced dementia, with heterogeneous trajectories in MCI. Beyond cognitive decline, disturbances in energy metabolism and neuroendocrine function often predate symptoms, linking metabolic status to AD risk-obesity and diabetes are recognized contributors, and weight loss may track with disease progression. The hypothalamus, a master regulator of systemic energy balance, emerges as a critical nexus; within it, hypothalamic tanycytes bridge blood and CSF, modulating signaling and metabolic homeostasis. Aging alters tanycyte transcription, and AD pathology further degrades tanycytes, potentially compromising tau clearance and homeostatic regulation. We propose an integrative approach combining transcriptomics with CSF and blood proteomics, clinical, metabolic, and neuroimaging data, and targeted animal experimentation to identify tanycyte- and hypothalamus-centered pathways linking metabolic dysregulation to AD progression, and to reveal novel biomarkers and therapeutic targets.

Alzheimer's disease (AD) features abnormal accumulation of Tau protein in the brain and cerebrospinal fluid (CSF) due to insufficient clearance into the blood. The precise mechanisms remain unclear. Using animal models, cell systems, and human tissues, we show that hypothalamic tanycytes in the median eminence-cells that connect blood and CSF-participate in Tau transport and AD pathogenesis. In mice, tanycytes internalize Tau from CSF and secrete it into pituitary portal capillaries, enabling entry into systemic circulation; disrupting tanycytic vesicular transport reduces CSF-to-blood Tau efflux and worsens Tau pathology. In AD patients, plasma-to-CSF ratios of total Tau and p-tau181 are lower. Tanycytes from postmortem AD brains exhibit severely fragmented processes and major transcriptomic changes, especially in vesicular-transport genes, explaining impaired clearance. These findings implicate tanycytic dysfunction in human AD and support a brain-to-blood tanycyte shuttle with broad implications for disease mechanisms and biomarkers.