Metabolic and hormonal deregulations are both a risk factor and a hallmark of Alzheimer's disease (AD) and frontotemporal dementia (FTD), occurring early in the course of the disease. In FTD in particular, hyperorality and dietary changes are associated with metabolic and hormonal changes such as altered levels of the anorexigenic hormone leptin.
The hypothalamus is a brain region that controls metabolism and hormonal systems. Hypothalamic function depends on its ability to sense peripheral signals. The hypothalamus sits on a circumventricular organ called the median eminence (ME) that puts it in contact with systemic blood circulation. In the ME, fenestrated capillaries allow the diffusion of bloodborne factors. However, despite the lack of blood-brain barrier at brain microvessels, diffusion is controlled by specialized ependymoglial cells, the tanycytes, which exert a barrier function between the ME and the third ventricle and controls the access of blood-borne molecules into the hypothalamus. Previous work from our laboratory and the ERC consortium has highlighted the role of tanycytes not only in the regulation of the release of neurohormones from neuroendocrine nerve terminals into the pituitary portal blood circulation, but also in the transport of circulating leptin into the hypothalamus. Hence hypothalamic dysfunction in AD and FTD can result either from dysregulation of neuroendocrine secretions, direct neuronal loss or from defective transport (and hence resistance) to hormones like leptin.
Our aim is to demonstrate that leptin transport though tanycytes is early altered in FTD and AD and correlates with metabolic and hormonal alterations, as well as with disease biomarkers.
Moreover, a recent study from our laboratory shows that gonadotropin or GnRH, the hormone that plays an essential role in the survival of our species by controlling the reproductive axis (the hypothalamic-pituitary-gonadal axis, or HPG) from minipuberty (first activation of the HPG after birth occurring as early as the second week of life), to male and female fertility through puberty, also plays a role in cognition and that the alteration of its secretion rate can lead to cognitive decline in certain conditions such as Down's syndrome (T21) and AD. Indeed, our preclinical studies in mouse models of T21 and AD show that an alteration of the pulsatility parameters of GnRH secretion, as evidenced by the alteration of the secretion profile of luteinizing hormone (LH) which is its proxy in the systemic circulation, accompanies cognitive decline and that pharmacological treatment with a subcutaneous pump delivering the natural hormone, GnRH, at the endogenous rate of littermates not carrying TS21 or AD, restores cognitive faculties to levels of mice not carrying the syndrome or the disease. A pilot study on 7 adult patients with T21, shows that the same pulsatile GnRH treatment increases cognition and markedly improves functional connectivity at rest of neuronal circuits known to be impaired in T21 after 6 months of treatment.
We will therefore take benefit of the ongoing BioWATCH study, which assesses hypothalamic function in patients with AD and FTD, to analyze GnRH pulsatility in a subset of participants. The main objective of the UPGRADE ancillary study is to demonstrate that pulsatile GnRH secretion is altered in AD, but also in other dementias such as frontotemporal dementia (FTD), and that this alteration correlates with clinical, imaging or biological markers. We ultimately aim at laying the groundwork for a pulsatile GnRH therapy in AD and FTD.
