Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer's disease by exerting anti-inflammatory and neuroprotective effects

In an aging society, Alzheimer’s disease (AD) exerts an increasingly serious health and economic burden. Current treatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underlie the decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires a multitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy that can be incorporated into a multitargeted treatment strategy. We used young (6-month-old) and adult (12-month-old) 3×Tg-AD mice that received ultramicronized PEA (um-PEA) for 3 months via a subcutaneous delivery system. Mice were tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potential neuropathological mechanisms were assessed postmortem by western blot, reverse transcription–polymerase chain reaction (RT-PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, and ameliorates both the depressive and anhedonia-like phenotype of 3×Tg-AD mice. Moreover, it reduces Aβ formation, the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus. Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrains neuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an early treatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potential to be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is already registered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use

Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis

Motor Neurone Disease Association (Malaspina/Apr13/817–791). Wellcome Trust support to a parallel study (Pathfinder Award, grant number 103208)

Targeting neuroinflammation in Alzheimer’s disease

Maria Rosanna Bronzuoli,1 Aniello Iacomino,2 Luca Steardo,1 Caterina Scuderi1 1Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Rome, Italy; 2Faculty of Psychology, University of Rome “G. Marconi”, Rome, Italy Abstract: Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed every 3.2 seconds. Alzheimer’s disease (AD) accounts for approximately 60%–80% of all dementia cases. Given this evidence, it is clear dementia represents one of the greatest global public health challenges. Currently used drugs alleviate the symptoms of AD but do not treat the underlying causes of dementia. Hence, a worldwide quest is under way to find new treatments to stop, slow, or even prevent AD. Besides the classic targets of the oldest therapies, represented by cholinergic and glutamatergic systems, β-amyloid (Aβ) plaques, and tau tangles, new therapeutic approaches have other targets. One of the newest and most promising strategies is the control of reactive gliosis, a multicellular response to brain injury. This phenomenon occurs as a consequence of a persistent glial activation, which leads to cellular dysfunctions and neuroinflammation. Reactive gliosis is now considered a key abnormality in the AD brain. It has been demonstrated that reactive astrocytes surround both Aβ plaques and tau tangles. In this condition, glial cells lose some of their homeostatic functions and acquire a proinflammatory phenotype amplifying neuronal damage. So, molecules that are able to restore their physiological functions and control the neuroinflammatory process offer new therapeutic opportunities for this devastating disease. In this review, we describe the role of neuroinflammation in the AD pathogenesis and progression and then provide an overview of the recent research with the aim of developing new therapies to treat this disorder. Keywords: reactive gliosis, astrocyte, microglia, Alzheimer’s diseas

Effect of palmytoilethanolamide in 3xTg-AD astrocytes as in vitro model of Alzheimer’s disease

Alzheimer's disease (AD) is a neurodegenerative disorder whose main features are β-amyloid (Aβ) plaques and neurofibrillary tangles, both responsible for neuronal loss and synapses reduction (DeKosky et al., 1996; Blennow et al., 2006). Recent studies have shifted their focus on another prominent hallmark, characteristic of AD patients, named “reactive gliosis”. Such a phenomenon is sustained by glia (and in particular by astrocytes) and characterized by a marked inflammatory response (Abramov et al., 2004; Heneka et al., 2010). Indeed, these morpho-functional changes can be observed studying cytoskeletal protein responsible for astrocytes functionality such as the glial fibrillary acidic (GFAP) (Verkhratsky and Butt, 2007), astrocyte-derived neurotrophins like S100β (Steiner et al., 2011), or pro-inflammatory mediators, like the cyclooxygenase-2 (COX-2) and the inducible nitric oxide synthase (iNOS) (Koistinaho et al., 2011). Among the models able to reproduce AD pathology, the 3×Tg-AD one, at present, is considered the most useful since it develops both senile plaques and neurofibrillary tangles (Oddo et al., 2003). Here, we used primary astrocytes obtained from 3xTg-AD and Non-Tg mice to study the effect of palmitoylethanolamide (PEA), an endogenous lipid compound, produced by central nervous system, mainly by glial cells. In the recent past, it has been demonstrated that PEA displays promising pharmacological properties (Calignano et al., 2001; Franklin et al., 2003; Skaper et al., 2014; Scuderi et al., 2012). Among these, the anti-inflammatory and neuroprotective actions, together with the extreme safety in humans (Petrosino and Di Marzo, 2016), seem to indicate it as a promising therapeutic strategy against AD. Results shown that primary 3×Tg-AD astrocytes are more reactive and produce higher levels of pro-inflammatory markers in comparison with cells deriving from Non-Tg animals. PEA resulted effective in modulating astrocytes reactivity, bringing all hallmarks to physiological values. Our results also confirmed the anti-inflammatory properties of PEA, since its ability to significantly reduce iNOS expression. The positive effects of PEA did not affect cell viability at all concentrations tested. Our interesting results prompt us to carry on further experiments to demonstrate that this molecule can actually represent a concrete therapeutic tool against AD

Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer's disease by exerting anti-inflammatory and neuroprotective effects.

In an aging society, Alzheimer's disease (AD) exerts an increasingly serious health and economic burden. Current treatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underlie the decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires a multitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy that can be incorporated into a multitargeted treatment strategy. We used young (6-month-old) and adult (12-month-old) 3×Tg-AD mice that received ultramicronized PEA (um-PEA) for 3 months via a subcutaneous delivery system. Mice were tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potential neuropathological mechanisms were assessed postmortem by western blot, reverse transcription-polymerase chain reaction (RT-PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, and ameliorates both the depressive and anhedonia-like phenotype of 3×Tg-AD mice. Moreover, it reduces Aβ formation, the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus. Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrains neuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an early treatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potential to be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is already registered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use