New Therapeutic Approach for Alzheimer's Disease By Targeting Brain Energy Metabolism

**New therapeutic approach for Alzheimer's disease by targeting brain energy metabolism**:

- Réf **ABG-128937**
- Sujet de Thèse
- 27/02/2025
- Autre financement public
- IRMETIST INSERM U1313
- Lieu de travail- Poitiers - Nouvelle Aquitaine - France
- Intitulé du sujet- New therapeutic approach for Alzheimer's disease by targeting brain energy metabolism
- Champs scientifiques- Santé, médecine humaine, vétérinaire
- Biologie
- Mots clés- Métabolisme cérébral, neuroprotection, maladie d'Alzheimer, lactate, FGF21

**Description du sujet**:
The brain accounts for just 2% of the human body's total mass, but consumes 25% of circulating glucose. It is the most energy-intensive organ in the body. The downside is that any pathology resulting in reduced cerebral glucose metabolism can rapidly lead to neuronal death, cognitive loss or severe brain damage. Over the past 20 years, we have shown that a significant proportion of this glucose is not directly consumed by neurons, but is taken up by astrocytes, transformed into lactate and then transferred to neurons. This lactate shuttle between astrocytes and neurons is necessary for neuronal activity. If lactate is a necessary substrate for neurons, can it be neuroprotective when the brain lacks glucose?

One of our aims is to demonstrate that lactate can restore cerebral energy metabolism and cognitive function after ischemic stroke, but also in Alzheimer's disease, pathologies which share a common impairment of cerebral glucose metabolism. Alzheimer's disease is characterized by a sharp drop in cerebral glucose consumption, even in the pre-symptomatic phase. Lactate administration will be tested in rodent models of this pathology. Longitudinal follow-up using MRI and behavioral tests will be carried out. This in vivo analysis will be coupled with in vitro studies on astrocyte cultures and neuron/astrocyte co-cultures to decipher the neuroprotective cellular mechanisms involved.

We also wish to develop a therapeutic approach based on our work on brain metabolism and lactate, and recent results on FGF21. This hormone, produced by the liver in response to metabolic stress, has been described as having an impact on brain metabolism. In particular, it promotes the use of alternative substrates to glucose (as lactate can be), to support brain activity during fasting. What's more, its anti-inflammatory and antioxidant effects could offer additional protection (compared to lactate) against the oxidative stress-related neuronal damage present in Alzheimer's disease. An interesting property of FGF21 is that it may also stimulate neuronal plasticity and improve cognition via the production of BDNF, while regulating mood and appetite, notably by reducing the attraction for sugar and alcohol. FGF21 has recently been shown to increase the expression of genes linked to the production and utilization of endogenous lactate, which is itself thought to be neuroprotective. This makes FGF21 (whose synthetic hormone exists and is injectable in humans) a promising therapeutic molecule for brain pathologies in which energy metabolism is impaired, as demonstrated in Alzheimer's disease.

**Prise de fonction**:

- 01/10/2025

**Nature du financement**:

- Autre financement public

**Précisions sur le financement**:

- Ministère / AAP Région Nouvelle Aquitaine; financement demandé

**Présentation établissement et labo d'accueil**:

- IRMETIST INSERM U1313

Unité IRMETIST - INSERM U1313 - Université de Poitiers

**Site web**:
**Ecole doctorale**:

- Ecole Doctorale Rosalind Franklin, Université de Poitiers- 16/05/2025