Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

Abstract

The pathogenesis of Alzheimer's disease (AD) is complex involving multiple contributing factors. The extent to which AD pathology impacts upon the metabolome is still not understood, nor is it known how disturbances change as the disease progresses. For the first time we have profiled longitudinally (6, 8, 10, 12 and 18 months) both the brain and plasma metabolome of APP/PS1 double transgenic and wild type (WT) mice. A total of 187 metabolites were quantified using a targeted metabolomics methodology. Multivariate statistical analysis produced models that distinguished APP/PS1 from WT mice at 8, 10 and 12 months. Metabolic pathway analysis found perturbed polyamine metabolism in both brain and blood plasma. There were other disturbances in essential amino acids, branched chain amino acids and also in the neurotransmitter serotonin. Pronounced imbalances in phospholipid and acylcarnitine homeostasis was evident in two age groups. AD-like pathology therefore impacts greatly on both the brain and blood metabolomes, although there appears to be a clear temporal sequence whereby changes to brain metabolites precede those in blood.

What success can teach us about failure: the plasma metabolome of older adults with superior memory and lessons for Alzheimer's disease

“…The biofluid matrix (e.g., plasma or serum) being interrogated via metabolomics, along with the molecular separation methods used (e.g., gas versus liquid chromatography) coupled with mass spectrometry for molecular identification, determines the specific yield of molecular species that can be used as a phenotypic readout. These data provide direct and/or indirect evidence for altered biochemical pathways linked to pathobiology (Pan et al, 2016) and brain structural (Ciavardelli et al, 2016) and functional (Cansev, 2016) integrity. The scope and depth of such molecular perturbations defined through metabolomics may ultimately empower individualized molecular phenotyping and our understanding of disease-specific mechanisms.…”

Metabolic network failures in Alzheimer's disease: A biochemical road map

“…Low levels of BCAAs have been implicated in hepatic insulin resistance in liver disease and may have a broader role in insulin resistance in the brain [77]. The seemingly paradoxical directionality difference in correlation of BCAAs with diabetes and cognition needs to be further evaluated in longitudinal studies taking into account weight changes, tissue type, and differences in human and animal model systems [28,78]. Our understanding of the biochemical crossroads between diabetes and AD could be greatly enhanced by metabolic profiling of both central and peripheral tissues in both diseases and over time.…”

“…An autopsy study of frontal cortex metabolites from AD patients versus controls showed six central metabolic pathways were altered along with glycerophospholipid metabolism and aspartate metabolism. A metabolomics study in an AD mouse model (APPswe/PS1deltaE9 double transgenic) found abnormalities in polyamine metabolism, essential amino acids, branched-chain amino acids (BCAAs), and serotonin, as well as phospholipid and acylcarnitine homeostasis with brain changes preceding those in the blood [28]. Although these studies highlight specific metabolic underpinnings of AD, not all metabolomics findings have been replicated.…”

Metabolomic Profiling of Bile Acids in Clinical and Experimental Samples of Alzheimer’s Disease

“…The extraction method applied to the samples was identical to our previously published work [22] using Biocrates p180 kits and based upon previous optimisation work undertaken by others [34]. Both human brain and mouse brain samples were collected into individual tubes to avoid cross-contamination, lyophilized, and cryogenically milled to a fine powder.…”

“…A range of metabolomic and lipidomic investigations of human AD and AD-like pathology have been undertaken. For example, studies have undertaken non-targeted profiling of polar metabolites [15,16,17,18] and non-polar (lipid) metabolites [19], and there has also been targeted profiling of fatty acids [20,21], phospholipids [7,22], and steroids [23]. However, no study as far as we are aware has focused exclusively on the profiling of bile acids.…”