Are Tanycytes the Missing Link Between Type 2 Diabetes and Alzheimer's Disease?

Abstract

Tanycytes are highly specialized bipolar ependymal cells that line the ventrolateral wall and the floor of the third ventricle in the brain and form a blood-cerebrospinal fluid barrier at the level of the median eminence. They play a pivotal role in regulating metabolic networks that control body weight and energy homeostasis. Due to the glucosensing function of tanycytes, they could be considered as a critical player in the pathogenesis of type 2 diabetes. Genetic fate mapping studies have established the role of tanycytes for the newly detected adult hypothalamic neurogenesis with important implications for metabolism as well as pathophysiology of various neurodegenerative diseases. We believe that a comprehensive understanding of the physiological mechanisms underlying their neuroplasticity, glucosensing, and cross talk with endothelial cells will enable us to achieve metabolic homeostasis in type 2 diabetes patients and possibly delay the progression of Alzheimer's disease and hopefully improve cognitive function.

Keywords: Alzheimer’s disease; Glucose homeostasis; Tanycytes; Type 2 diabetes.

Figure 1:. Alzheimer’s Disease, Diabetes and Tanycyte Axis:

Normal healthy functioning pancreas maintains normal homeostasis by regulating insulin synthesis, insulin signalling, facilitating glucose uptake and metabolism. As a result, in the normal brain there is maintenance of the normal blood brain barrier, normal neurogenesis, neuroregeneration, normal Aβ synthesis and clearance, normal memory and normal cognitive function. However, in type 2 diabetes, the normal insulin synthesis and insulin signaling becomes impaired thereby leading to hyperglycemia, inflammation, increased oxidative stress, islet amyloid polypeptide (IAPP), reactive oxygen species (ROS), nitric oxide (NO) production and generation of advanced glycation products and mitochondrial dysfunction. As a result, tanycytes as well as pancreatic β cells become dysfunctional thereby initiating a cascade of events in the brain involving neuroinflammation, secretion of inflammatory cytokines, blood brain barrier breakdown, increased amyloid beta (Aβ) synthesis, decreased Aβ clearance, formation of amyloid plaques and neurofibrillary tangles. Cumulative effects lead to neuronal loss, neurodegeneration, impaired microglial function, loss of memory and cognitive dysfunction as observed in AD patients. Perusal of literature suggest that intracerebroventricular injection of either fibroblast growth factor 1 (FGF1), FGF19, FGF21 or FGFR1/β-klotho bispecific antibody (bFKB1) has the potential to improve the diabetic phenotype by modulating tanycyte as well as pancreatic beta cell functions. We propose that transplantation of embryonic stem (ES) and induced pluripotent stem (iPS) cell-derived insulin producing cells (IPCs) and tanycytes can reverse hyperglycemia and delay or possibly halt the progression of AD thereby improving cognitive function.

Figure 2:. Derivation of functional tanycytes from ES and iPS cells:

The derivation of tanycytes from the ES and iPS cells has not yet been attempted. We propose that the lineage commitment and the directed differentiation of ES and iPS cells into tanycytes can be achieved in vitro. A simplified version of the directed differentiation as depicted in our scheme has the potential to generate an unlimited source and supply of tanycytes. The ES and iPS cell-derived tanycytes can be successfully used to study their normal physiological function using 3D organoids, as well as to develop disease in a dish model, perform genome editing to decipher functional genomics, neuroepigenomics, proteomics, high throughput screening of chemical libraries for novel drug discovery as well as transplantation and in vivo transdifferentiation studies to develop tanycyte-based regenerative therapies to treat type 2 diabetes and AD.