Alzheimer's brains show inter-related changes in RNA and lipid metabolism

Abstract

Alzheimer's disease (AD) involves changes in both lipid and RNA metabolism, but it remained unknown if these differences associate with AD's cognition and/or post-mortem neuropathology indices. Here, we report RNA-sequencing evidence of inter-related associations between lipid processing, cognition level, and AD neuropathology. In two unrelated cohorts, we identified pathway-enriched facilitation of lipid processing and alternative splicing genes, including the neuronal-enriched NOVA1 and hnRNPA1. Specifically, this association emerged in temporal lobe tissue samples from donors where postmortem evidence demonstrated AD neuropathology, but who presented normal cognition proximate to death. The observed changes further associated with modified ATP synthesis and mitochondrial transcripts, indicating metabolic relevance; accordingly, mass-spectrometry-derived lipidomic profiles distinguished between individuals with and without cognitive impairment prior to death. In spite of the limited group sizes, tissues from persons with both cognitive impairment and AD pathology showed elevation in several drug-targeted genes of other brain, vascular and autoimmune disorders, accompanied by pathology-related increases in distinct lipid processing transcripts, and in the RNA metabolism genes hnRNPH2, TARDBP, CLP1 and EWSR1. To further detect 3′-polyadenylation variants, we employed multiple cDNA primer pairs. This identified variants that showed limited differences in scope and length between the tested cohorts, yet enabled superior clustering of demented and non-demented AD brains versus controls compared to total mRNA expression values. Our findings indicate inter-related cognition-associated differences in AD's lipid processing, alternative splicing and 3′-polyadenylation, calling for pursuing the underlying psychological and therapeutics implications.

Longitudinal Basal Forebrain Degeneration Interacts with TREM2/C3 Biomarkers of Inflammation in Presymptomatic Alzheimer's Disease

“…Cholinergic neurons can react to neuropathology through pretranscriptional and post-transcriptional regulation of ChAT, and possibly ApoE (Soreq and Seidman, 2001;Soreq, 2015). Recent RNA-sequencing work identified upregulated lipid processing transcripts in the temporal lobe of patients with AD neuropathology but no cognitive decline at the time of death (Barbash et al, 2017), suggesting possible involvement of ApoE in other brain regions vulnerable to early AD. With intact lipid metabolism (e.g., in an APOE 4 Ϫ genetic background), these endogenous mechanisms might sustain central cholinergic integ- Figure 6.…”

Glycerophosphatidylcholine PC(36:1) absence and 3′-phosphoadenylate (pAp) accumulation are hallmarks of the human glioma metabolome

“…Lipidomics is an exciting new area 26 . It has been widely applied in several disciplines, including neuroblastoma 27 , mammalian cancer 28 , prostate cancer 29 , tetrahydrocannabinol addiction 30 , Alzheimer’s Disease 31 and drug development 32 .…”

Bayesian integrative analysis of epigenomic and transcriptomic data identifies Alzheimer's disease candidate genes and networks

“…Among the differential genes in Table 1 are the neurotransmitter transporters SLC6A9 and SLC6A12, which were associated with cognition in human AD patients and AD model systems [52][53][54]. A recently developed SLC6A9 inhibitor is currently tested in a clinical trial [55].…”