In vivo hippocampal ³¹P NMR metabolites in Alzheimer's disease and ageing

Abstract

Memory loss is the most common early symptom of Alzheimer's disease (AD). For this study, we chose the hippocampi as regions of interest. The hippocampus, which is closely associated with memory processing, is known to be vulnerable to damage in the early stage of AD. We considered both inter-group (patients vs controls) and intra-group (right vs left hippocampus) comparisons. We examined seven patients meeting the DSM-III-R criteria of senile dementia and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS - ADRDA) criteria of probable AD, and II aged controls. This study focused on the measurement of phosphorus 31 ((31)P) Nuclear Magnetic Resonance (NMR) spectroscopy metabolites in each hippocampus. We found significant differences in phosphorus metabolites for both intra-group comparison (pH shifted towards relative alkalosis in the left hippocampus of patients) and inter-group consideration (reduced phosphodiesters [Pde]and elevated gamma adenosine triphosphate (ATP) in the right hippocampus, higher inorganic phosphate (pHi) in the left hippocampus for patients as compared to controls). We suggest energy failure and membrane functional breakdown in patients compared to aged controls.

Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model

“…Earlier studies have shown that connexin hemichannels, which are the main constituents of ATP release 51 , are upregulated via Abdependent mechanisms in astrocytes particularly around Ab plaques in FAD mouse models 54 , that is, in the areas where astroglial hyperactivity was highest in our study. Moreover, studies in AD patients have demonstrated increased levels of ATP in plaque-bearing brain regions compared with age-matched nondemented control individuals 31,55 . Overall, these data suggest that in addition to hyperactivity mediated by P2Y1 receptor upregulation, increased release of ATP through astroglial connexin hemichannels also contributes to astroglial network dysfunction.…”

Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer's disease

“…Also the increase in glutamate levels observed after perinatal brain ischemia was strongly reduced when Cx43 HCs were inhibited by mimetic peptides (Li et al, ); the consequence of such Cx43 targeting was a reduction of neuronal death and brain infarct size as well as an improved functional recovery (Davidson et al, ; Davidson, Green, Nicholson, Bennet, & Gunn, ; Li et al, ). In AD patients, increased level of ATP was measured in plaque bearing brain areas compared to that in control patients (Mecheri et al, ) and in FAD mice, ATP and glutamate release was higher than in WT mice (Delekate et al, ; Yi et al, ). Knocking out Cx43 in astrocytes of APP/PS1 mice reduced the levels of ATP and glutamate with a concomitant reduction in neuronal suffering (Yi et al, ).…”

Mapping of Hippocampal pH and Neurochemicals from in vivo Multi-Voxel 31P Study in Healthy Normal Young Male/Female, Mild Cognitive Impairment, and Alzheimer's Disease

“…For Parkinson's disease studies, no significant change was found in the mean pH during activation or recovery, although, in normal subjects, the mean pH increased significantly during activation [8]. In another clinical study, hippocampus pH measurements were performed on seven AD patients (n = 7) using single voxel (ISIS) technique ( 31 P experimental time for both left and right hippocampus was 32 minutes) and reported significant pH changes in the left hippocampus of AD subjects as compared to control subjects [9]. However in that same report [9], the 31 P peaks were not well resolved and ␤-ATP was not detectable.…”

“…In another clinical study, hippocampus pH measurements were performed on seven AD patients (n = 7) using single voxel (ISIS) technique ( 31 P experimental time for both left and right hippocampus was 32 minutes) and reported significant pH changes in the left hippocampus of AD subjects as compared to control subjects [9]. However in that same report [9], the 31 P peaks were not well resolved and ␤-ATP was not detectable. The graphical presentation of pH changes in various brain disorders is shown in Fig.…”