Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid deposition.

Alzheimer's disease (AD) is characterized by amyloid-β deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition. Here, we studied the impact of cannabinoid receptor type 1 (CB1) deficiency on the development of AD pathology by breeding amyloid precursor protein (APP) Swedish mutant mice (APP23), an AD animal model, with CB1-deficient mice.

Oxidative stress resistance in hippocampal cells is associated with altered membrane fluidity and enhanced nonamyloidogenic cleavage of endogenous amyloid precursor protein.

Reactive oxygen species (ROS) have important roles as signaling molecules in the regulation of a variety of biological processes. On the other hand, chronic oxidative stress exerted by ROS is widely considered a causative factor in aging. Therefore, cells need to be able to adapt to a chronic oxidative challenge and do so to a certain cell-type-specific extent.

Adaptation of neuronal cells to chronic oxidative stress is associated with altered cholesterol and sphingolipid homeostasis and lysosomal function.

Chronic oxidative stress has been causally linked to several neurodegenerative disorders. As sensitivity for oxidative stress greatly differs between brain regions and neuronal cell types, specific cellular mechanisms of adaptation to chronic oxidative stress should exist. Our objective was to identify molecular mechanisms of adaptation of neuronal cells after applying chronic sublethal oxidative stress.

Increased connexin 43 expression as a potential mediator of the neuroprotective activity of the corticotropin-releasing hormone.

CRH is a major central stress mediator, but also a potent neuroprotective effector. The mechanisms by which CRH mediates its neuroprotective actions are largely unknown. Here, we describe that the gap junction molecule connexin43 (Cx43) mediates neuroprotective effects of CRH toward experimentally induced oxidative stress.

Effects of sulindac sulfide on the membrane architecture and the activity of gamma-secretase.

gamma-Secretase is a membrane-embedded multi-protein complex that catalyzes the final cut of the Alzheimer's disease-related amyloid precursor protein (APP) to amyloid-beta peptides of variable length (37-43 amino acids) via an unusual intramembrane cleavage. Recent findings propose that some commonly used non-steroidal anti-inflammatory drugs (NSAIDs) have the ability to modulate specifically gamma-secretase activity without inhibiting the enzyme as a whole. These drugs may shift the processing of APP from the longer amyloid-beta 42 peptide towards shorter, less fibrillogenic and less toxic amyloid-beta species.

Cholesterol-like effects of selective cyclooxygenase inhibitors and fibrates on cellular membranes and amyloid-beta production.

Strong evidence suggests a mechanistic link between cholesterol metabolism and the formation of amyloid-beta peptides, the principal constituents of senile plaques found in the brains of patients with Alzheimer's disease. Here, we show that several fibrates and diaryl heterocycle cyclooxygenase inhibitors, among them the commonly used drugs fenofibrate and celecoxib, exhibit effects similar to those of cholesterol on cellular membranes and amyloid precursor protein (APP) processing. These drugs have the same effects on membrane rigidity as cholesterol, monitored here by an increase in fluorescence anisotropy.

Functional disassociation of the central and peripheral fatty acid amide signaling systems.

Fatty acid amides (FAAs) constitute a large class of endogenous signaling lipids that modulate several physiological processes, including pain, feeding, blood pressure, sleep, and inflammation. Although FAAs have been proposed to evoke their behavioral effects through both central and peripheral mechanisms, these distinct signaling pathways have remained experimentally challenging to separate. Here, we report a transgenic mouse model in which the central and peripheral FAA systems have been functionally uncoupled.

Increased seizure susceptibility and proconvulsant activity of anandamide in mice lacking fatty acid amide hydrolase.

A number of recent in vitro studies have described a role for endogenous cannabinoids ("endocannabinoids") as transsynaptic modulators of neuronal activity in the hippocampus and other brain regions. However, the impact that endocannabinoid signals may have on activity-dependent neural events in vivo remains mostly unknown and technically challenging to address because of the short half-life of these chemical messengers in the brain. Mice lacking the enzyme fatty acid amide hydrolase [FAAH (-/-) mice] are severely impaired in their ability to degrade the endocannabinoid anandamide and therefore represent a unique animal model in which to examine the function of this signaling lipid in vivo.