Bioenergetics and inflammation: novel insights for new therapeutic approaches in Alzheimer's Disease

Alzheimer’s Disease (AD) is the most common form of dementia characterized by chronic and progressive neurodegeneration resulting in severe cognitive, memory, and behavioral impairment. The neurodegeneration observed in AD involves early synaptotoxicity, neurotransmitter disturbances, mitochondrial structural and functional changes accumulation of extracellular β-amyloid (Aβ) deposits and intracellular neurofibrillary tangles, gliosis and only at later stages overt neuronal cells loss and associated brain atrophy. Neuroinflammatory changes are increasingly emerging as players in both initiation and progression of this disease. Neuroinflammation, in turn, might promote and/or worsen alterations in global and regional brain metabolism and energetics in the pathogenesis of cognitive impairment and AD [1]. The relationship between neuroinflammation, abnormalities in brain metabolism and the pathogenesis of AD are not fully defined yet. Mitochondria are severely affected in AD and greatly contribute to neuronal dysfunction and loss. Hence, during AD, mitochondria go through profound alterations, which impair ATP content and increase reactive oxygen species (ROS) levels. Recently, we found that glutamate can sustain cell metabolism both in both physiological and pathological settings, through the activity of Na+/Ca2+exchanger (NCX) and Na+ dependent Excitatory Amino Acids Transporters (EAATs). Additionally, K+-selective ion channels (particularly of the Kv7 family) identified in mitochondrial membranes play a role in controlling mitochondrial metabolism and energy homeostasis. 
On these bases, the major aim of this project is to test the hypothesis that treatments that reduce neurodegeneration by targeting neuroinflammation and/or by regulating neuronal metabolism, energy balance and bioenergetics might reduce the progression of AD. Among these target for pharmacotherapies, we have identified peroxisome proliferator-activated receptors alpha (PPARα), receptors involved in protection from neuroinflammation and regulation of cellular bioenergetics, immunoneutralization of TNF Related Apoptosis Inducing Ligand (TRAIL), a pleiotropic proinflammatory molecule with prominent neurotoxic properties, and modulators of Kv7 channels.
To this aim, we have designed a multidisciplinary approach whereby both cells models and transgenic mice models of AD (3xTg-AD mice) will be utilized.
In in vitro models of AD neurodegeneration, we will characterize the effects of glutamate supplementation, the interaction with NCX and the role of EAAT/NCX pathway. Additionally, we will explore the possibility that imbalances in mitochondrial Kv7 channels functions might by implicated in AD neurodegeneration. In these cell models we will also test drugs that modulate Kv7 channels and PPARα agonists.
In in vivo models of AD, as neuroinflammation contributes to AD neuropathology and exacerbates the AD progression, AD transgenic mice will be exposed in adulthood to the viral mimic polyriboinosinic-polyribocytidilic acid (PolyI:C), a synthetic analog of double-stranded RNA, which stimulates the immune system. In these animals, we will characterize the effect of inflammation on the progression of AD and the neuroinflammatory mechanisms underlying glutamate imbalance and activation of the kynurenine pathway in the CNS. Additionally, we will test the efficacy of peripheral immunomodulation by anti-TRAIL antibodies and the effect of a PPARα agonist and Kv7 modulators. The progression of the disease will be assessed by monitoring markers of inflammation and specific AD markers, by behavioral tests and electrophysiological recording from frontal cortex neurons.
We expect to identify and characterize novel target for AD in mitochondria and highlight mechanistic relationships between neuroinflammation, glutamate metabolism and neuronal bioenergetics that can lead to innovative therapies. 
Our project has a strong translational potential, as PPARα agonist (fibrates) have been utilized in humans for decades for lipid metabolism disorders and Kv7 channels modulators, retigabine and flupirtine, have been used for the treatment of epilepsy and pain, respectively.