Evaluation of Metabolic and Synaptic Dysfunction Hypotheses of Alzheimer's Disease (AD): A Meta-Analysis of CSF Markers

Abstract

Background:Alzheimer’s disease (AD) is currently incurable and a majority of investigational drugs have failed clinical trials. One explanation for this failure may be the invalidity of hypotheses focus-ing on amyloid to explain AD pathogenesis. Recently, hypotheses which are centered on synaptic and met-abolic dysfunction are increasingly implicated in AD.Objective:Evaluate AD hypotheses by comparing neurotransmitter and metabolite marker concentrations in normal versus AD CSF.Methods:Meta-analysis allows for statistical comparison of pooled, existing cerebrospinal fluid (CSF) marker data extracted from multiple publications, to obtain a more reliable estimate of concentrations. This method also provides a unique opportunity to rapidly validate AD hypotheses using the resulting CSF con-centration data. Hubmed, Pubmed and Google Scholar were comprehensively searched for published Eng-lish articles, without date restrictions, for the keywords “AD”, “CSF”, and “human” plus markers selected for synaptic and metabolic pathways. Synaptic markers were acetylcholine, gamma-aminobutyric acid (GABA), glutamine, and glycine. Metabolic markers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies that measured markers in AD and controls (Ctl), provided means, standard er-rors/deviation, and subject numbers were included. Data were extracted by six authors and reviewed by two others for accuracy. Data were pooled using ratio of means (RoM of AD/Ctl) and random effects meta-analysis using Cochrane Collaboration’s Review Manager software.Results:Of the 435 identified publications, after exclusion and removal of duplicates, 35 articles were in-cluded comprising a total of 605 AD patients and 585 controls. The following markers of synaptic and met-abolic pathways were significantly changed in AD/controls: acetylcholine (RoM 0.36, 95% CI 0.24-0.53, p<0.00001), GABA (0.74, 0.58-0.94, p<0.01), pyruvate (0.48, 0.24-0.94, p=0.03), glutathione (1.11, 1.01-1.21, p=0.03), alanine (1.10, 0.98-1.23, p=0.09), and lower levels of significance for lactate (1.2, 1.00-1.47, p=0.05). Of note, CSF glucose and glutamate levels in AD were not significantly different than that of the controls.Conclusion:This study provides proof of concept for the use of meta-analysis validation of AD hypothe-ses, specifically via robust evidence for the cholinergic hypothesis of AD. Our data disagree with the other synaptic hypotheses of glutamate excitotoxicity and GABAergic resistance to neurodegeneration, given ob-served unchanged glutamate levels and decreased GABA levels. With regards to metabolic hypotheses, the data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and anaple-rosis of the tricarboxylic acid cycle using glutamate. Future applications of meta-analysis indicate the pos-sibility of further in silico evaluation and generation of novel hypotheses in the AD field.

Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy

“…The dual targeting of VEGFA and Ang2 was shown previously to increase M2 to M1-like skewing, which is indicative of a proinflammatory macrophage activation (22,24,25). In other studies, durable antitumor responses observed upon combining CD40 agonism with anti-CSF1R antibodies (36) or small-molecule CSF1R inhibitors (37,48) were attributed to the reduction of immunosuppressive M2-like TAMs and the simultaneous induction of polyfunctional inflammatory M1-like TAMs producing TNFα, IL-6, and IL-12. In our study, we observed a more pronounced effect on TAM depletion after anti-CD40 therapy in MC38 tumors compared to others (36).…”

Multi-Tissue Neocortical Transcriptome-Wide Association Study Implicates 8 Genes Across 6 Genomic Loci in Alzheimer’s Disease

“…al [63] found that increasing CLPTM1 levels decreased miniature inhibitory postsynaptic potentials, while reciprocally, decreasing CLPTM1 levels elevated GABA currents in the post-synaptic neuron, strongly suggesting that CLPTM1 negatively regulates GABAergic signaling. A recent literature meta-analysis looking at neurotransmitter synaptic dysregulation in AD, found decreased levels GABA in AD patients, supporting the potential dysregulation of GABAergic signaling in AD [65] Far less is known about CEACAM19, and any biological connection to AD. What work has been done is predominantly focused upon oncology.…”

Altered Brain Metabolome Is Associated with Memory Impairment in the rTg4510 Mouse Model of Tauopathy

“…Some authors reported higher CSF glutamate values in AD patients than in controls [42,43], whereas others reported decreased values [44,45] or no changes at all [46][47][48]. A recent study using C13-glutamine performed in APP/PS1 mice suggests that reduced glutamine uptake and impaired oxidative glutamine metabolism could be very early markers of AD pathogenesis, as they precede the amyloid plaque formation in this model [49]. This hypothesis may be plausible in the rTg4510 mouse of the AD model at an early pathological stage.…”