*Review* **Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders**

**Martina Assogna 1,2, Francesco Di Lorenzo <sup>1</sup> , Alessandro Martorana 1,2 and Giacomo Koch 1,3,\***


**\*** Correspondence: g.koch@hsantalucia.it

**Abstract:** Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and in patients' studies. In the last few years, palmitoylethanolamide (PEA), an endogenous lipid mediator, and its new composite, which is a formulation constituted of PEA and the well-recognized antioxidant flavonoid luteolin (Lut) subjected to an ultra-micronization process (co-ultraPEALut), has been identified as a potential therapeutic agent in different disorders by exerting potential beneficial effects on neurodegeneration and neuroinflammation by modulating synaptic transmission. In this review, we will show the potential therapeutic effects of PEA in animal models and in patients affected by neurodegenerative disorders.

**Keywords:** PEA; neuroinflammation; neurodegeneration; synaptic plasticity; frontotemporal dementia; Alzheimer's disease; amyotrophic lateral sclerosis; transcranial magnetic stimulation; endocannabinoids

### **1. Introduction**

As life expectancy is continuously rising, the global economic effect of neurodegenerative disorders, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is increasing significantly [1]. The pathogenic mechanisms driving neurodegenerative illnesses, however, are still unknown. Several factors are involved, including genetic, environmental, and endogenous influences. Pathophysiological causes include abnormal protein dynamics, oxidative stress with reactive oxygen species, mitochondrial dysfunction, DNA damage, synaptic deficits, and neuroinflammatory processes [2].

Neuroinflammation is a complex process mediated by cytokines, which are primarily generated by microglia and astrocytes and whose activation can be harmful or protective to neurons. When implicated in the induction and control of neuronal development, cell survival, and synaptic plasticity pathways, beneficial pro-inflammatory cytokines are protective. Prolonged and abnormal pro-inflammatory signaling, however, is responsible for tissue neurodegeneration [3].

From a neuropathological point of view, neurodegenerative diseases are characterized by the deposition of misfolded proteins, such as amyloid beta (Aβ) and tau aggregates for AD and TAR DNA-binding protein 43 (TDP-43) in ALS and FTD. The progressive accumulation of these proteins triggers various pathological phenomena that contribute to the pathophysiological cascade of events that lead to the onset of clinical symptoms. Especially the impairment of the synaptic efficacy and the trigger and sustenance of neuroinflammation processes are increasingly being studied in neurodegenerative disorders as it has been shown their pivotal role in the progression of neurodegeneration and their potential modulation as therapeutic target in neurodegenerative diseases.

**Citation:** Assogna, M.; Di Lorenzo, F.; Martorana, A.; Koch, G. Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders. *Biomolecules* **2022**, *12*, 1161. https://doi.org/10.3390/ biom12081161

Academic Editors: Salvatore Cuzzocrea and Rosalia Crupi

Received: 17 June 2022 Accepted: 6 August 2022 Published: 22 August 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

The aim of this review is to give insights into the interplay between synaptic machinery and neuroinflammation processes in neurodegenerative disorders and to clarify how palmitoylethanolamide (PEA)—an endogenous lipid mediator with high affinity for endocannabinoid receptor—and its new composite—which is a formulation constituted of PEA and the well-recognized antioxidant flavonoid luteolin (Lut) subjected to an ultramicronization process (co-ultraPEAlut)—might be able to modulate this relationship in animal models and in patients.

#### *1.1. Synaptic Impairment and Neuroinflammation in Neurodegenerative Disorders*

#### 1.1.1. Alzheimer's Disease

#### Synaptic Impairment

AD is macroscopically characterized by brain atrophy while microscopic hallmarks are the deposition of amyloid plaques and neurofibrillary tangles. Recently, with the introduction of biomarkers able to reflect in vivo the neuropathological alterations occurring in the disease, substantial modifications have been posed to AD definition; however, the clinical course of the disease remains unpredictable due to the scarce comprehension of pathophysiological mechanisms.

At this regard, there is strong evidence that synaptic density loss occurs before neuronal death, implying that impaired synaptic plasticity processes play a major role in AD etiology [4,5]. The loss of synaptic density has been reported to have the strongest statistical link with the degree of cognitive impairment in AD, rather than Aβ plaques, tangle formation, or neuronal death [6].

As a result, synaptic transmission impairment caused by toxic oligomeric species [7] can predict disease severity more accurately than gross neuronal death—a later occurrence establishing synaptic dysfunction as a fundamental driver of AD-related cognitive decline rather than a byproduct [8]. Indeed, experimental studies in AD animal models have shown that Aβ peptides and tau proteins interact with physiological mechanisms of neuronal synaptic plasticity [9,10].

Moreover, N-methyl-d-aspartate receptor (NMDAr) mediated glutamatergic neurotransmission is crucial for synaptic plasticity and survival of neurons. Nevertheless, excessive NMDAr activity, mediated by excessive Ca2+ influx, may result in excitotoxicity and promotes cell death underlying a potential mechanism of neurodegeneration [11]. In humans, neurophysiological techniques, such as transcranial magnetic stimulation (TMS), can help in differentiating different neurodegenerative diseases [12] and forecast AD disease progression by estimating cortical functioning at a specific time [13].

TMS can be used to examine cortical plasticity mechanisms, such as long-term potentiation (LTP), one of the most important neurophysiological correlates for learning and memory [14]. We previously demonstrated that AD patients had a consistent deficit of LTP-like cortical plasticity in motor function [15,16] and the cerebellar cortex [17], with a sparing of mechanisms of long-term depression (LTD), evident also in early mild cognitive impairment (MCI) patients [18].

Moreover, in AD animal models, the synaptic dysfunction has been linked to a disorder of high-frequency neuronal oscillatory activity, in particular in the gamma range (40 Hz) [19,20]. Accordingly, in a recent work, TMS combined with EEG (TMS-EEG) recordings have shown that AD patients had more prominent decrease in gamma activity in the prefrontal cortex with a stronger impairment of LTP-like plasticity mechanisms and more prominent cognitive decline [21]. Interestingly, the optogenetic entrainment of fast-spiking parvalbumin-positive interneurons of AD animal model at gamma frequencies was able to reduce the total amyloid levels, probably acting on both neurons and microglia [22].

Similarly, intranasal administration of pro-resolving lipid mediator in a mouse model of AD was able to improve memory dysfunction and restore gamma oscillation impairment, accompanied by a modulation of microglial activation [23].

#### Neuroinflammation in AD they play a vital part in the inflammatory process of the central nervous system.

Neuroinflammation in AD

[22].

*Biomolecules* **2022**, *12*, x 3 of 17

impairment, accompanied by a modulation of microglial activation [23].

Microglial cells are a primary target of neurodegenerative disease research because they play a vital part in the inflammatory process of the central nervous system. Depending on the specific stimulus the microglia have been exposed to, it could maintain a balance between a pro-inflammatory status (M1 phenotype), characterized by the synthesis of inflammatory cytokines, such as interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF), and the synthesis and release of anti-inflammatory cytokines (IL-4, IL-8, and IL-10) and neurotrophic factors (M2 phenotype) [24]. Thus, the complex involvement of inflammatory cytokines in both neurodegeneration and neuroprotection is far from complete in such a complex environment. Amyloid peptides, comprising both oligomeric and senile plaque forms, are thought to be the key inflammatory trigger in AD. A prolonged pro-inflammatory signaling caused by amyloid mis-metabolism, in particular, can result in an overproduction of pro-inflammatory cytokines involved in neurodegenerative pathways signaling [3]. While there is evidence that persistent neuroinflammation causes an increase in amyloid synthesis [25], a clear relationship between tau pathology and neuroinflammation is still unclear. We recently showed that human astrocytes cultures incubated with cerebrospinal fluid (CSF) samples from AD patients were vulnerable in terms of increased apoptosis only in the presence of high levels of tau protein and APOE4 genotype [26]. Depending on the specific stimulus the microglia have been exposed to, it could maintain a balance between a pro-inflammatory status (M1 phenotype), characterized by the synthesis of inflammatory cytokines, such as interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF), and the synthesis and release of anti-inflammatory cytokines (IL-4, IL-8, and IL-10) and neurotrophic factors (M2 phenotype) [24]. Thus, the complex involvement of inflammatory cytokines in both neurodegeneration and neuroprotection is far from complete in such a complex environment. Amyloid peptides, comprising both oligomeric and senile plaque forms, are thought to be the key inflammatory trigger in AD. A prolonged pro-inflammatory signaling caused by amyloid mis-metabolism, in particular, can result in an overproduction of pro-inflammatory cytokines involved in neurodegenerative pathways signaling [3]. While there is evidence that persistent neuroinflammation causes an increase in amyloid synthesis [25], a clear relationship between tau pathology and neuroinflammation is still unclear. We recently showed that human astrocytes cultures incubated with cerebrospinal fluid (CSF) samples from AD patients were vulnerable in terms of increased apoptosis only in the presence of high levels of tau protein and APOE4 genotype [26]. As a result of these observations, we hypothesized that tau proteins play a substantial

was able to reduce the total amyloid levels, probably acting on both neurons and microglia

Similarly, intranasal administration of pro-resolving lipid mediator in a mouse model of AD was able to improve memory dysfunction and restore gamma oscillation

Microglial cells are a primary target of neurodegenerative disease research because

As a result of these observations, we hypothesized that tau proteins play a substantial role in astrocyte degradation and a proinflammatory role in APOE4 patients [27]. Surprisingly, APOE4 carriers have been found to have an imbalanced flipping of the microglial phenotype M1–M2 [28]. Furthermore, microglial apolipoprotein E (ApoE) regulates microglial homeostatic gene expression downstream, resulting in a neurodegenerative phenotypic switch that could exacerbate AD pathogenesis [29]. Consistent with this framework, we showed that during early phases of AD, in APOE4 carriers, amyloid pathology likely induces a specific cytokines pattern synthesis associated to cognitive preservation [30] (Figure 1). role in astrocyte degradation and a proinflammatory role in APOE4 patients [27]. Surprisingly, APOE4 carriers have been found to have an imbalanced flipping of the microglial phenotype M1–M2 [28]. Furthermore, microglial apolipoprotein E (ApoE) regulates microglial homeostatic gene expression downstream, resulting in a neurodegenerative phenotypic switch that could exacerbate AD pathogenesis [29]. Consistent with this framework, we showed that during early phases of AD, in APOE4 carriers, amyloid pathology likely induces a specific cytokines pattern synthesis associated to cognitive preservation [30] (Figure 1).

**Figure 1. Neuroinflammation and synaptic impairment in AD:** Panel (**A**) displays the interplay among the neuron and the glial cells involved in AD pathology, such as astrocyte, microglia, and oligodendrocyte. In the dotted square, the particular of synaptic transmission impairment induced by Aβ and p-Tau activation; panel (**B**) shows the probable mechanisms of action of the activated microglia and astrocyte induced by amyloid beta deposition and the pro-inflammatory cytokines cascade in the pathophysiology of AD. AD: Alzheimer's disease; Aβ: amyloid beta; p-Tau: phosphorylated tau.
