Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Abstract

Neuronal cell loss underlies the pathological decline in cognition and memory associated with Alzheimer disease (AD).Recently, targeting the endocannabinoid system in AD has emerged as a promising new approach to treatment. Studies have identified neuroprotective roles for endocannabinoids against key pathological events in the AD brain, including cell death by apoptosis. Elucidation of the apoptotic pathway evoked by ␤-amyloid (A␤) is thus important for the development of therapeutic strategies that can thwart A␤ toxicity and preserve cell viability. We have previously reported that lysosomal membrane permeabilization plays a distinct role in the apoptotic pathway initiated by A␤. In the present study, we provide evidence that the endocannabinoid system can stabilize lysosomes against A␤-induced permeabilization and in turn sustain cell survival. We report that endocannabinoids stabilize lysosomes by preventing the A␤-induced up-regulation of the tumor suppressor protein, p53, and its interaction with the lysosomal membrane. We also provide evidence that intracellular cannabinoid type 1 receptors play a role in stabilizing lysosomes against A␤ toxicity and thus highlight the functionality of these receptors. Given the deleterious effect of lysosomal membrane permeabilization on cell viability, stabilization of lysosomes with endocannabinoids may represent a novel mechanism by which these lipid modulators confer neuroprotection. Alzheimer disease (AD)2 is a debilitating illness of the brain defined by the progressive deterioration of cognition and memory as a result of selective neuronal loss in the hippocampus and surrounding areas of the cerebral cortex (1). There is substantial evidence to suggest that at least a subset of neurons in the AD brain die by apoptosis (2). The principal neuropathological hallmark of the disease, ␤-amyloid peptide (A␤), has been shown to induce apoptosis in neuronal cells in vivo and in vitro (3, 4) through a variety of enzymatic pathways that include activation of caspase-3 (5), calpain (6, 7), and lysosomal cathepsins (8, 9).Recently, the lysosomal system has been implicated in AD pathogenesis (9, 10). Neurons of AD patients demonstrate alterations in the lysosomal system, including the cellular pathways that converge on it, namely endocytosis and autophagy (10, 11). Such alterations include an increase in the size and number of endosomes (10, 12), autophagosomes (13) and lysosomes (10) and an increase in the gene expression and synthesis of all classes of lysosomal hydrolases, including cathepsins (14). In addition to their role in the digestion of cellular waste, it has become clear that partial and selective lysosomal membrane permeabilization (LMP), followed by the release of lysosomal enzymes into the cytosol, can induce apoptotic cell death (15). Cathepsins D and L are among the lysosomal proteases that have been implicated in apoptosis by virtue of their ability to activate apoptotic effectors, such as mitochondrial uncoupling and caspases (16).Among the agents that are ca...

The Endocannabinoid, Anandamide, Augments Notch-1 Signaling in Cultured Cortical Neurons Exposed to Amyloid-β and in the Cortex of Aged Rats

“…Culture of Cortical Neurons-Primary cortical neurons were prepared as described previously (27). Briefly, 1-day-old male Wistar rats were decapitated in accordance with institutional and national ethical guidelines, and their cerebral cortices were removed.…”

“…Numb (Nb), the negative regulator of the Notch pathway, makes neurons more vulnerable to the deleterious effects of A␤ by altering calcium homeostasis (24) and up-regulating the p53 tumor suppressor protein (25,26), signaling events that we have previously described to be pertinent in the neurodegeneration evoked by A␤, the neuropathological peptide that accumulates in AD (27).…”

The endocannabinoid system in normal and pathological brain ageing

“…A significant part of the intracellular CB1 receptors is present at lysosomes and late endosomes [167,168]. Cannabinoids at physiological concentrations increase lysosomal stability and integrity [169]. On the other hand, D 9 -THC in high concentration can increase lysosomal permeability through CB1 receptor binding, which may contribute to the neurotoxic effect of the drug [170].…”

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

“…Huntington's disease [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. The neuroprotective effects of cannabinoids are mediated through CB1 receptors, located in neurons, which modulate neuronal function, and CB2 receptors, mostly located in microglia, which play an important role in neuroinflammation.…”