Prevention of Alzheimer's Disease

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Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation

AbstractAlzheimer's disease (AD) is characterized by enhanced -amyloid peptide (A) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after A treatment, both in vivo and in vitro. Here, we show that senile plaques in AD patients express cannabinoid receptors CB₁ and CB₂, together with markers of microglial activation, and that CB₁-positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation. In pharmacological experiments, we found that G-protein coupling and CB₁ receptor protein expression are markedly decreased in AD brains. Additionally, in AD brains, protein nitration is increased, and, more specifically, CB₁ and CB₂ proteins show enhanced nitration. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 to rats prevent A-induced microglial activation, cognitive impairment, and loss of neuronal markers. Cannabinoids (HU-210, WIN55,212-2, and JWH-133) block A-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor- release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB₂-selective agonist. Moreover, cannabinoids abrogate microglia-mediated neurotoxicity after A addition to rat cortical cocultures. Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.






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Introduction

Alzheimer's disease (AD), the most common form of dementia, is characterized by the deposition of -amyloid peptide (A) within one of its pathological hallmarks: the senile plaque. Activated microglia cluster at senile plaques (McGeer et al., 1987; Dickson et al., 1988), and this seems to be responsible for the ongoing inflammatory process in the disease. Transgenic mouse models of AD also develop plaques in which A deposits and activated microglia exist (Masliah et al., 1996; Frautschy et al., 1998; Jantzen et al., 2002). Furthermore, microglial activation results in neurodegeneration both in vitro (Meda et al., 1995; Gao et al., 2002; Xie et al., 2002) and in vivo (Weldon et al., 1998; Herrera et al., 2000; Iravani et al., 2002) paradigms. In this context, recent studies have focused on the therapeutic interest of limiting microglial activation and inflammation in AD and other neurological disorders.

Cannabinoids, the active components of marijuana and their analogs, exert a wide spectrum of central and peripheral effects by activating specific cannabinoid receptors, two of which have been well characterized to date: CB₁ and CB₂ (Howlett et al., 2002; Piomelli, 2003). CB₁ receptors are found in high density in the nervous system (Herkenham et al., 1990), in which they mediate cannabinoid psychoactivity, and all types of neural cells express them. Thus, in addition to being present in neurons, CB₁ receptors exist in astrocytes (Bouaboula et al., 1995; Snchez et al., 1998), microglia (Waksman et al., 1999; Walter et al., 2003), and oligodendrocytes (Molina-Holgado et al., 2002). In contrast, the CB₂ receptor is considered to be expressed solely in cells and organs of the immune system and is unrelated to cannabinoid psychoactivity. There are also recent reports on the existence of CB₂ receptors in microglia (Walter et al., 2003) and on cannabinoids affecting migration (Walter et al., 2003), as well as nitric oxide (NO) and cytokine production (Waksman et al., 1999; Puffenbarger et al., 2000; Facchinetti et al., 2003) in microglial cell cultures in vitro.

Cannabinoids exert neuroprotection under different experimental conditions. Thus, cannabinoid receptor activation protects hippocampal or granule cerebellar neurons from excitotoxicity (Skaper et al., 1996; Shen and Thayer, 1998; Hampson and Grimaldi, 2001) and from hypoxia and glucose deprivation (Nagayama et al., 1999). In vivo, cannabinoids decrease hippocampal neuronal loss and infarct volume after cerebral ischemia (Nagayama et al., 1999), acute brain trauma (Panikashvili et al., 2001), and ouabain-induced excitotoxicity (van der Stelt et al., 2001). These effects have been ascribed to inhibition of glutamate transmission, reduction of calcium influx, and subsequent inhibition of noxious cascades, such as tumor necrosis factor- (TNF-) generation and oxidative stress.

This background prompted us to study the characteristics and localization of cannabinoid receptors in AD brain, with particular emphasis on any relationship with microglial activation. Furthermore, the effects of cannabinoid receptor activation were studied in an animal model of AD in vivo and in a model of A-induced microglial activation in vitro.


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