Despite the progress made in the description and diagnosis, no effective medication to prevent or treat Alzheimer's disease (AD) exists so far; thus novel therapeutic targets for the development of new treatments are urgently needed.
We focus on a heterogeneous family of bioactive lipid signals, the N-acylethanolamides (NAEs), whose endogenous levels can be enhanced by the pharmacological inhibition of their metabolism and whose physiological roles might ensure a multilevel intervention for AD treatment.
The best characterized NAEs are the endocannabinoid anandamide, acting mainly on CB1 receptors, and palmitoylethanolamide and oleoylethanolamide, two potent activators of PPARalpha. Both CB1 and PPARalpha receptors play a key role in several molecular and cellular aspects of neurodegeneration/neuroprotection.
FAAH is the key enzyme metabolizing NAEs in the brain and its expression and activity resulted increased in several neuroinflammatory/neurodegenerative conditions, including AD.
We hypothesize that the pharmacological inhibition of FAAH might provide a novel approach for the development of an effective therapy for AD.
We aim to test our hypothesis in vitro and in vivo, focusing at different molecular, cellular and behavioural levels and addressing the impact of FAAH inhibition on both the early onset and the late progression of AD neuropathology.
To this aim, we will use a triple transgenic model of AD that harbors three mutant human genes (APPswe, PS1M146V, and tauP301L), develops amyloid plaques and neurofibrillary pathology, age-related cognitive decline, impairment in synaptic plasticity and closely mimic the disease progression in humans. In these mice we will evaluate whether the increased tone of endogenous NAEs produced by the chronic treatment with the FAAH inhibitor PF-3845 might have beneficial effects on the neurofunctional alterations and exert potential neuroprotective/neuroregenerative effects.
In the last 30 years the history of research for an AD therapy has followed three different tentative strategies: replacement therapy, disease modification, and multi-level intervention (Cappa, 2018 Front Neurology). These strategies rather than stages in an evolutionary process, are still playing a central role in current research.
The first approach is linked to the identification of the presence of cognitive deficits and neuropsychiatric symptoms, possibly reflecting specific neurotransmitter dysfunctions, which can become the target of a specific replacement therapy. This concept relies on the prediction that drugs increasing defective neurotransmission in the AD brain could be expected to result in a symptomatic treatment of the neurofunctional hallmarks of AD.
The search for a disease-modifying treatment (DMT) for AD was motivated by advances in the understanding of neurodegenerative mechanisms in AD in areas, such as neurotrophic factors, protein processing, oxidative stress, and inflammatory processes. The main focus of DMT approaches has centered on the amyloid cascade hypothesis (ACH), which attributes a central role in neuronal degeneration and cognitive decline to the pathological aggregation of amyloid ß (Aß) peptides, predominantly Aß40 and Aß42. The failure of several large-scale trials based on therapeutic approaches aimed at enhancing Aß clearance or modulating its production has generated some legitimate disappointment, but has also provided important lessons and has contributed to the rise of the so-called ¿tau hypothesis¿ that shares most of the conceptual assumptions of the amyloid approach, i.e., the idea that the development of AD could be stopped or delayed by interfering with a primary pathological event, i.e., in this case the formation of neurofibrillary tangles.
Considering dementia as the irreversible outcome of a linear sequence of events unleashed by pathological protein aggregation inevitably leads to the consideration that pathophysiological process leading to dementia begins many years prior to overt clinical manifestations of disease. An early step in this direction was the definition of a ¿pre-dementia¿ stage of AD, mild cognitive impairment (Cappa, 2018 Front Neurology). This change of perspective was instrumental in the development of new diagnostic criteria and suggested that the failures of drugs acting on the ACH might be attributed to their failure to address the disease process at the earliest possible stages, i.e., before neurodegeneration has taken place.
Another important revolutionary perspective in AD research is that the ¿neuron-centric, linear cascade initiated by Aß and leading to dementia¿ (Cappa, 2018 Front Neurology), implying direct causation, should be revised. AD is a brain disorder, which needs to be investigated at all the multiple levels (cells, networks, computations) intervening between genes and molecules and the clinical phenotype (Cappa, 2018 Front Neurology). At the molecular and cellular level, this is now acknowledged by approaches considering the complex interplay of neuronal changes with responses of astrocytes, microglia, and of the vascular compartment (Cappa, 2018 Front Neurology). An increased consideration of the contributing role of neuroinflammation, metabolic modifications, including stress reaction and of neuroprotective agents is testified by the presence of 25% of drugs involving these mechanisms of action under investigation. The quest for effective drugs targeting protein accumulation can be integrated in a multimodal perspective, considering different levels of intervention at the same time, including treating inflammatory reactions, modulating network dysfunction, and acting on cognitive and psychiatric symptoms.
In this project we propose to focus on a heterogeneous family of bioactive lipid signals, the N-acylethanolamides (NAEs), whose endogenous levels can be easily enhanced by the pharmacological inhibition of their metabolism and whose physiological roles might ensure a multilevel intervention for AD treatment.
The results from the proposed project may offer a novel perspective, based on the combination of the three therapeutical strategies at the same time. In fact, NAEs, particularly anandamide, were shown to regulate several neurotransmissions (glutammatergic, monoaminergic, GABAergic); to control neuroinflammatory/neurodegenerative processes and to improve behavioral symptoms (both cognitive and non-cognitive) of AD.