Neuron-astrocyte interplay in neurodegenerative disorders: preclinical experience with
Caterina Scuderi, PhD
Dept. Physiology and Pharmacology “V. Erspamer”
SAPIENZA Universty of Rome
In the last decade, the neuron-centric vision of neuropsychiatric diseases has undergone
considerable changes. Indeed, it is now clear that the non-neuronal cells could be involved in the
pathogenesis and progression of many diseases due to their important and active roles exerted in the brain physiological and pathological conditions. Therefore these cells could not be considered
simple co-stars in the drama of neuropsychiatric disorders, including neurodegeneration.
Glial cells are the most abundant cells in the central nervous system (CNS). These cells consist of a heterogeneous cell population, which comprises astrocytes, oligodendrocytes, microglia, and NG2-
positive cells. Although each of these cell groups has common features, a marked variability has
been highlighted in their functions in different brain regions and during brain development.
Despite the profound differences among the cells of the glia, they all work to preserve the structural integrity and functionality of the brain. Astrocytes represent the most abundant and morphologically heterogeneous glial cells, and they are involved in a remarkable number of active functions of the CNS. These cells are responsible for a wide variety of complex and essential functions in the brain.
For these reasons, astrocytes are often defined as “homeostatic glial cells.” In a novel point of view,
astrocytes cannot be just considered as passive supportive cells deputed to preserve neuronal
activity and survival. Nowadays, it is recognized that many levels of brain homeostasis are under
their control and that astroglial cells could be correctly considered as the brain defense agents.
Given their pleiotropic functions, it is not surprising that their dysfunction is an important
contributor to neurological disorders.
It has been well established that brain insults trigger a specific astroglial reaction represented by a complex morphofunctional remodeling. Indeed, astrocytes rapidly act in response to pathology
undergoing important changes in their morphology and functioning. This reactive state starts with
the intention to control and remove the brain damage, however it has deleterious consequences. In
fact, reactive gliosis is a self-perpetuating process which, at the end, exacerbates the injury and, on another hand it represents a non-physiologic state in which astrocytes lose their helpful properties.
Palmitoylethanolamide and Alzheimer’s
These events are particularly patent in Alzheimer’s disease (AD) brain, and Alzheimer himself was
able to recognize, in autoptic specimens, a marked activation of astroglial cells and described a
manifest inflammatory status.
AD is a neurodegenerative disorder characterized by memory loss and significant cognitive decline
with impaired activities of daily living. Despite all scientific efforts, all medications currently used provide only modest and transient benefits to a subset of patients and effective pharmacotherapeutic options are lacking. Histopathologically, the hallmarks of AD are extracellular deposits of beta amyloid (Aβ) fibrils in senile plaques (SP) and intraneuronal neurofibrillary tangles (NFT). Aβ results from the abnormal proteolytic cleavage of amyloid-precursor protein by the sequential action of beta- and gamma-secretase. The widely accepted Aβ cascade hypothesis suggests that this peptide is the direct cause of neurodegeneration, synaptic loss and cognitive decline in AD. Even if several biochemical mechanisms have been proposed, including production of reactive oxygen species, disruption of calcium homeostasis, activation of Wnt pathway, excitotoxicity, activation of apoptotic pathways, neuronal degeneration, and neurotransmitter deficits, the precise role of abnormal protein aggregates in the pathogenesis of AD remains to be clarified. Interestingly, data from both animal models and human autopsy of AD have demonstrated that reactive astrocytes colocalize with both SP and NFT suggesting that the primary aim of this peculiar localization is probably the creation of a barrier between healthy and injured tissue. Recent evidence assigns to astrocyte dysfunctions a critical role in aging and in several neurodegenerative diseases, including AD. Several brain injuries, including Aβ deposition, modify astrocyte physiological functioning and they acquire a reactive phenotype. Activation of these cells is fundamentally a protective response aimed at removing injurious stimuli. However, uncontrolled and prolonged activation goes beyond physiological control and detrimental effects override the beneficial ones. In this condition, Aβ peptides accumulation promote neuroinflammation, accounting for the synthesis of different
cytokines and pro-inflammatory mediators. After their release, pro-inflammatory signal molecules
act, in an autocrine way, to self perpetuate reactive gliosis and, in a paracrine way, to kill
neighboring neurons expanding the neuropathological damage. In this context, it is important to
highlight that inflammatory process, once initiated, may contribute independently to neural
dysfunction and cell death, thereby establishing a self-fostering vicious cycle, by which the
inflammation represents a primary cause of further neurodegeneration. Therefore, it is reasonable to assume that early combination of neuroprotective and anti-inflammatory treatments aimed at
restoring astrocyte functions may represent an appropriate approach to treat AD, whereas the
treatment of only one pathological process might even worsen the others.
Along this direction, in the last years our research group is looking for possible compounds able to fulfill the criteria of a multi-factorial therapeutic approach. In this context, palmitoylethanolamide (PEA) has attracted much attention for its proven anti-inflammatory and neuroprotective properties reported in many neuropathological conditions other than AD. PEA, a naturally occurring amide of ethanolamine and palmitic acid, is a lipid messenger that mimics several endocannabinoid-driven actions, even though it does not bind to cannabinoid receptors. PEA is abundant in the CNS and it is conspicuously produced by glial cells. Many of its beneficial properties have been considered to be dependent on the activation of the peroxisome proliferator-activated receptor-alpha (PPAR-α). In recent reports we showed the ability of PEA to attenuate in vitro the Aβ-induced up-regulation of a wide range of inflammatory mediators by interacting at the PPAR-α nuclear site. These encouraging results prompted us to explore the anti-inflammatory and neuroprotective effects of PEA in an in vivo model of AD. We found that Aβ infusion in rat hippocampus results in severe changes of biochemical markers related to reactive gliosis, amyloidogenesis, and tau protein hyperphosphorylation. Interestingly, systemic administration of PEA was able to restore the Aβ- induced alterations through PPAR-α involvement. In addition, results from the Morris water maze task highlighted a mild cognitive deficit during the reversal learning phase of the behavioral study.
Similarly to the biochemical data, also mnestic deficits were reduced by PEA treatment.
These data disclose novel findings about the therapeutic potential of PEA, and suggest novel
strategies that hopefully could have the potential not just to alleviate the symptoms but also to
modify disease progression. Considering the extreme safety and tolerability of PEA in humans, our
findings offer new opportunity in the already fruitless world of AD treatment.