Positive association between plasmatic levels of orexin A and the endocannabinoid-derived 2-arachidonoyl lysophosphatidic acid in Alzheimer’s disease

Abstract

A regular sleep-wake cycle plays a positive function that preserves synaptic plasticity and brain activity from neuropathological injuries. The hypothalamic neuropeptide orexin-A (OX-A) is central in sleep-wake regulation and has been found to be over-expressed in the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD) suffering from sleep disturbances. OX-A promotes the biosynthesis of 2-arachidonoylglycerol (2-AG), which, in turn, could be phosphorylated to 2-arachidonoyl lysophosphatidic acid (2-AGP). The reorganization of the actin cytoskeleton during neurite retraction is one of the best-characterized effects of lysophosphatidic acids. However, less information is available regarding the reorganization of the neuronal microtubule network in response to OX-A-induced 2-AG and, possibly consequent, 2-AGP production in AD patients. This is of special relevance also considering that higher 2-AG levels are reported in the CSF of AD patients. Here, we found a positive correlation between OX-A and 2-AGP concentrations in the plasma, and an increase of 2-AGP levels in the CSF of AD patients. Furthermore, a negative correlation between the plasmatic 2-AGP levels and the mini-mental state examination score is also revealed in AD patients. By moving from the human patients to in vitro and in vivo models of AD we investigated the molecular pathway linking OX-A, 2-AG and 2-AGP to the phosphorylation of pT231-Tau, which is a specific early plasma biomarker of this disorder. By LC-MS analysis we show that OX-A, via OX-1R, induces 2-AG biosynthesis via DAGLα, and in turn 2-AG is converted to 2-AGP in primary hippocampal neurons. By confocal microscopy and western blotting assay we found an OX-A- or 2-AGP-mediated phosphorylation of Tau at threonine 231 residue, in a manner prevented by LPA1R (2-AGP receptor) or OX1R (OX-A receptor) antagonism with AM095 or SB334867, respectively. Finally, by patch-clamp recording we documented that 2-AGP-mediated pT231-Tau phosphorylation impairs glutamatergic transmission in the mouse hippocampus. Although further additional research is still required to clarify the potential role of orexin signaling in neurodegeneration, this study provides evidence that counteraction of aberrant OX-A signaling, also via LPA-1R antagonism, may be beneficial in the mild-to-moderate age-related cognitive decline associated with sleep disturbances.

Relationship between sex, APOE genotype, endocannabinoids and cognitive change in older adults with metabolic syndrome during a 3-year Mediterranean diet intervention

“…Our results are consistent with studies showing that 2-AG concentrations are elevated in the plasma samples of AD patients [ 17 , 94 ] and in the brain samples of AD mouse models [ 95 ], and that elevated 2-AG may aggravate synapse impairment in AD [ 96 ] and obese mouse models [ 97 , 98 ]. Cross-sectional studies also support the inverse correlation between 2-AG concentrations and cognitive performance, in cognitively normal individuals [ 15 , 16 ] or those with AD [ 17 ].…”

“…The role of eCBs in cognitive processes has been extensively studied in animal models [ 11 , 14 ]. However, evidence in humans is limited, with studies pointing to beneficial, detrimental, or null effects of eCBs in cognitively normal individuals [ 15 , 16 ] or those with AD [ 17 , 18 ]. Moreover, although plasma concentrations of eCBs are assumed to reflect their overall availability throughout the body, there is still controversy about whether they are reliable biomarkers of brain eCB signaling [ 19 ].…”

The wake- and sleep-modulating neurons of the lateral hypothalamic area demonstrate a differential pattern of degeneration in Alzheimer’s disease

“…In parallel with increased Orx csf levels, plasma Orx levels also demonstrated elevated levels in AD patients 53 . Pharmacological manipulation of the orexinergic neurotransmitter system across various animal models has demonstrated neuroprotective potential.…”

“…Moreover, the extent of cognitive impairment was more pronounced in AD patients with various neuropsychiatric with elevated Orx csf levels 15,20 . In parallel with increased Orx csf levels, plasma Orx levels also demonstrated elevated levels in AD patients 53 . Pharmacological manipulation of the orexinergic neurotransmitter system across various animal models has demonstrated neuroprotective potential.…”

“…A decline in ATP1B1 expression may lead to hyperexcitability and an excitotoxic cellular response-mediated neurodegeneration 67,70 . Increased Orx levels have also been associated with tau hyperphosphorylation (T231) in primary hippocampal pyramidal neurons, which HCRTR1 inhibitor SB334867 reverted 53 . Further investigations are warranted to ascertain whether Orxinergic neuronal vulnerability arises solely from pathological stress or from an augmented production to maintain the overall orexinergic system in the brain.…”