Figure 1.

Interaction of glutamate activity on alterations in anxiety and depression levels characteristic of the disease. (A) Pathogenic mechanisms based on the activity of the excitatory neurotransmitter glutamate both at synaptic and extrasynaptic levels, which could explain the elevated perception of anxiety and depression described in Alzheimer's disease (AD). At the synaptic level, in the animal model of the disease 3xTgAD mice the activation of mGluR2/3 receptors due to excess glutamate (red dots), has been linked to the formation of β-amyloid peptides with 42 residues long (Aβ42), while at the extrasynaptic level, it has been linked to high glutamate levels, which can increase the activation of its NMDA receptors (eNMDAR), producing an increase in inflammation. Both processes have been linked to the presence of anxiety and depression. (B) Proposed mechanisms of action of a ketogenic diet (KD) in the improvement of perception of anxiety and depression in patients with AD. (1) The production of ketone bodies derived from the intake of KDs act as glutamate inhibitors in the NMDA extrasynaptic receptor (eNMDAR), decreasing the extrasynaptic activity of glutamate (red dots) and, as a consequence, the inflammation. (2) They are also capable of blocking the toxicity derived from the formation of amyloid plaques, whose production is partly due to the activation of the mGluR2/3 glutamate receptors. (3) Moreover, they could improve the activity of glutamate at a synaptic level because of a greater ATP contribution (with regard to glucose metabolism), which would have a positive impact on the cognitive and emotional capacity. (4) Finally, the neuroprotector effect of ketone bodies (as a result of the improvement in the electron chain functioning) could lessen the levels of oxidative stress and inflammation. All these processes achieve a decrease in the perception of anxiety and depression, characteristic of this pathology.