CORDIS - Risultati della ricerca dell’UE

Targeting Inflammation and Neurogenesis using cannabinoids to delay the onset of Alzheimer’s disease

Final Report Summary - NGINFAD (Targeting Inflammation and Neurogenesis using cannabinoids to delay the onset of Alzheimer’s disease)

It has been suggested in previous studies that the stimulation of the endocannabinoid system (ES) using the synthetic compound WIN contributes to preserve cognition in aging rats. These effects were likely mediated by the anti-inflammatory properties of this ES agonist, which reduced the production of inflammatory cytokines and promoted neurogenesis in the brain. The logical conclusion of these studies was that WIN was beneficial in preventing cognitive decline. From the above it follows that stimulating the ES could also have beneficial effects in the pathological brain (e.g. Alzheimer’s disease), where neuroinflammation is thought to exacerbate the progression of the pathology. This working hypothesis constituted the backbone of the NGINFAD project and it has been tested accordingly. The first set of data in cellulo comforted the hypothesis, since short periods of WIN incubation reduced glial reactivity in primary cocultures of mouse astrocytes and microglial cells isolated from 5xFAD mice, the AD mouse model used in the laboratory. These data are interesting because they pointed out glial cells as an important target for WIN anti-inflammatory properties, likely independent of a non-exclusive potential neuronal-driven effect. Then, we translated the question in vivo into the 5xFAD mouse model, for which we characterized a progressive increase of the inflammatory condition across time (at 2, 4 and 6 months), with increased expression of pro-inflammatory markers/mediators (GFAP, IL-1β, CCL2, C3, MMP-2, MMP-12…). Note that as they age, 5xFAD mice recapitulate most pathological signs and behavioural dysfunctions of Alzheimer’s disease, including accumulation of beta amyloid (Aβ, neuroinflammation, neuronal death and learning impairment. The anti-inflammatory effects of WIN observed in cellulo were not reproduced when the endocannabinoid agonist was chronically injected for 4 weeks in young adult 5xFAD mice (3 months), during a “prodromal-like” phase of the pathology. To our surprise, WIN not only was unable to prevent or limit inflammation in these animals, but on the contrary it stimulated inflammation. Indeed, WIN chronic infusion promoted glial reactivity and the expression of major pro-inflammatory cytokines such as IL-1β and TNF-α. Most interestingly, WIN treatment did not affect the number of amyloid plaques, but augmented the levels of Aβ oligomers. The latter are increasingly seen as the most neurotoxic assemblies of Aβ, likely responsible for synaptic dysfunctions in the early phases of the disease that precede irreversible damage. In this context, we could predict that WIN effects will likely lead to a deterioration of the pathological and cognitive outcome.

One important conclusion of the present work is that stimulation of the ES per se does not necessarily improves the outcome of the pathology, but may on the contrary aggravate it. Therefore, the present data do not support previous reports suggesting beneficial effects of ES stimulation in another Alzheimer’s transgenic mouse model, the Tg2576. In this case, mice were treated for 4 months at relatively old ages (11 months) as compared with 1-month treatment at between 3 and 4 months of age in our case. Our results also suggest that the effects of WIN administration in pathological conditions may differ from those induced when administered during physiological aging. Moreover, it has to be noted that 5xFAD mice display an early and marked inflammation and Aβ accumulation starting between 2 and 4 months of age, while the Tg2576 mice present a weaker phenotype, even when they are older (11 months). It is plausible that ES stimulation in the 5xFAD rather synergizes with a strong ongoing inflammation, which may ultimately cause an exacerbation of Aβ accumulation, in particular of oligomeric assemblies.