Tag Archives: Alzheimer’s disease

The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells.

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“Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. A massive accumulation of beta-amyloid (Abeta) peptide aggregates has been proposed as pivotal event in AD. Abeta-induced toxicity is accompanied by a variegated combination of events including oxidative stress… Cannabidiol, a non-psychoactive marijuana component, has been recently proposed as an antioxidant neuroprotective agent in neurodegenerative diseases. Moreover, it has been shown to rescue PC12 cells from toxicity induced by Abeta peptide. Here, we report that cannabidiol inhibits hyperphosphorylation of tau protein in Abeta-stimulated PC12 neuronal cells, which is one of the most representative hallmarks in AD… These results provide new molecular insight regarding the neuroprotective effect of cannabidiol and suggest its possible role in the pharmacological management of AD, especially in view of its low toxicity in humans.”

http://www.ncbi.nlm.nih.gov/pubmed/16389547

 

Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement.

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“In view of the pro-inflammatory scenario observed in Alzheimer’s disease, in the recent years anti-inflammatory drugs have been proposed as potential therapeutic agents. We have previously shown that cannabidiol, the main non-psychotropic component from Cannabis sativa, possess a variegate combination of anti-oxidant and anti-apoptotic effects that protect PC12 cells from Abeta toxicity. In parallel, cannabidiol has been described to have anti-inflammatory properties in acute models of inflammation …

The here reported data increases our knowledge about the possible neuroprotective mechanism of cannabidiol, highlighting the importance of this compound to inhibit beta-amyloid induced neurodegeneration, in view of its low toxicity in humans.”

http://www.ncbi.nlm.nih.gov/pubmed/16490313

Effects of cannabinoids on the immune system and central nervous system: therapeutic implications.

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“Cannabinoids possess immunomodulatory activity, are neuroprotective in vivo and in vitro and can modify the production of inflammatory mediators… Cannabinoid-induced immunosuppression may have implications for the treatment of neurological disorders that are associated with excess immunological activity, such as multiple sclerosis and Alzheimer’s disease. There is anecdotal evidence that cannabis use improves the symptoms of multiple sclerosis, and studies with animal models are beginning to provide evidence for the mechanism of such effects. The development of nonpsychotropic cannabinoid analogues and modulators of the metabolism of endogenous cannabinoid ligands may lead to novel approaches to the treatment of neurodegenerative disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/18031185

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

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“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 betaA treatment, both in vivo and in vitro. Here, we show that senile plaques in AD patients express cannabinoid receptors CB1 and CB2……

…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.”

Free full text: http://www.jneurosci.org/content/25/8/1904.long

Microglial interaction with beta-amyloid: implications for the pathogenesis of Alzheimer’s disease.

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Abstract

“The etiology of Alzheimer’s disease (AD) involves a significant inflammatory component as evidenced by the presence of elevated levels of a diverse range of proinflammatory molecules in the AD brain. These inflammatory molecules are produced principally by activated microglia, which are found to be clustered within and adjacent to the senile plaque. Moreover, long-term treatment of patients with non-steroidal anti-inflammatory drugs has been shown to reduce risk and incidence of AD and delay disease progression. The microglia respond to beta-amyloid (Abeta) deposition in the brain through the interaction of fibrillar forms of amyloid with cell surface receptors, leading to the activation of intracellular signal transduction cascades. The activation of multiple independent signaling pathways ultimately leads to the induction of proinflammatory gene expression and production of reactive oxygen and nitrogen species. These microglial inflammatory products act in concert to produce neuronal toxicity and death. Therapeutic approaches focused on inhibition of the microglial-mediated local inflammatory response in the AD brain offer new opportunities to intervene in the disease.”

http://www.ncbi.nlm.nih.gov/pubmed/11455613

In search of a treatment for Alzheimer’s disease and potential immunonosuppresive therapeutic interventions.

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Abstract

“Alzheimer’s disease (AD) is a serious neurodegenerative disease of aging. Recent projections of the dramatic increase in AD incidence worldwide by 2050 reveal its magnitude as a world-wide health crisis and underscore the urgent need to understand the etiology of AD in order to develop therapeutic interventions. A popular debate among scientists has traditionally pitted those in support of Beta amyloid protein as a causative factor (“Baptists”) against others who implicate tau hyperphosphorylation (“Tauists”). Considering the significance of Beta amyloid protein and hyperphosphorlyated tau protein aggregates in AD pathology, this article delves into the nature of inflammation associated with these aggregates. Aspects of inflammation focus on microglia, resident immune cells of the CNS that are activated during AD inflammation and are known to play a significant role in pathogenesis. This article discusses the role of microglia, inflammation, and the immune response as a middle ground in the debate between the “Tauists” and the “Baptists” respective positions. It explores recent advances in immunotherapy and supports continued research in and use of immunosuppressive regimens as potential therapeutic interventions for AD.”

http://www.ncbi.nlm.nih.gov/pubmed/18766151

An amyloid β42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer’s disease.

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“The endocannabinoids and their attending cannabinoid (CB)(1) receptors have been implicated in the control of cognition, but their possible roles in dementias are still unclear.

 The results suggest that an Aβ(42)-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD.”

http://www.ncbi.nlm.nih.gov/pubmed/21546126

Alzheimer’s disease and Notch signaling.

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Abstract

“Cleavage of the amyloid precursor protein (APP) by gamma-secretase generates a neurotoxic amyloid beta-peptide (Abeta) that is thought to be associated with the neurodegeneration observed in Alzheimer’s disease (AD) patients. Presenilin is the catalytic member of the gamma-secretase proteolytic complex and mutations in presenilins are the major cause of early-onset familial Alzheimer’s disease. In addition to APP, gamma-secretase substrates include Notch1 homologues, Notch ligands Delta and Jagged, and additional type I membrane proteins, raising concerns about mechanism-based toxicities that might arise as a consequence of inhibiting gamma-secretase. Notch signaling is involved in tumorigenesis as well as in determining the fates of neural and nonneural cells during development and in adults. Alterations in proteolysis of the Notch by gamma-secretase could be involved in the pathogenesis of AD. Inconsistently, several recent observations have indicated that enhanced Notch signaling and expression could be instrumental in neurodegeneration in AD. Therefore, detailed and precise study of Notch signaling in AD is important for elucidating diverse mechanisms of pathogenesis and potentially for treating and preventing Alzheimer’s disease.”

http://www.ncbi.nlm.nih.gov/pubmed/19853579

The endocannabinoid, anandamide, augments Notch-1 signaling in cultured cortical neurons exposed to amyloid-β and in the cortex of aged rats.

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“Aberrant Notch signaling has recently emerged as a possible mechanism for the altered neurogenesis, cognitive impairment, and learning and memory deficits associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in models of AD has emerged as a potential approach to slow the progression of the disease process. Although studies have identified neuroprotective roles for endocannabinoids, there is a paucity of information on modulation of the pro-survival Notch pathway by endocannabinoids. In this study the influence of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol, on the Notch-1 pathway and on its endogenous regulators were investigated in an in vitro model of AD. We report that AEA up-regulates Notch-1 signaling in cultured neurons… In summary, AEA has the proclivity to enhance Notch-1 signaling in an in vitro model of AD, which may have relevance for restoring neurogenesis and cognition in AD.”

http://www.ncbi.nlm.nih.gov/pubmed/22891244

Role of the endocannabinoid system in Alzheimer’s disease: new perspectives.

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Abstract

“The role of the endocannabinoid system in several diseases is currently under intense study. Among these, Alzheimer’s disease may be a new promising area of research. We have recently reported the existence of profound changes in the location and density of several elements of this system in Alzheimer’s disease tissue samples, indicating that a non-neuronal endocannabinoid system is up-regulated in activated glia. Additional data from other groups suggest that glial cells may be important elements in the regulation of endocannabinoid system activity, both in health as in disease. Some of these aspects are briefly discussed in the present review.”

http://www.ncbi.nlm.nih.gov/pubmed/15306158