Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer's-Like Pathology.
The relationship between long-term cholinergic dysfunction and risk of developing dementia is poorly understood. Here we used mice with deletion of the vesicular acetylcholine transporter (VAChT) in the forebrain to model cholinergic abnormalities observed in dementia. Whole-genome RNA sequencing of hippocampal samples revealed that cholinergic failure causes changes in RNA metabolism. Remarkably, key transcripts related to Alzheimer's disease are affected. BACE1, for instance, shows abnormal splicing caused by decreased expression of the splicing regulator hnRNPA2/B1. Resulting BACE1 overexpression leads to increased APP processing and accumulation of soluble Aβ1-42. This is accompanied by age-related increases in GSK3 activation, tau hyperphosphorylation, caspase-3 activation, decreased synaptic markers, increased neuronal death, and deteriorating cognition. Pharmacological inhibition of GSK3 hyperactivation reversed deficits in synaptic markers and tau hyperphosphorylation induced by cholinergic dysfunction, indicating a key role for GSK3 in some of these pathological changes. Interestingly, in human brains there was a high correlation between decreased levels of VAChT and hnRNPA2/B1 levels with increased tau hyperphosphorylation. These results suggest that changes in RNA processing caused by cholinergic loss can facilitate Alzheimer's-like pathology in mice, providing a mechanism by which decreased cholinergic tone may increase risk of dementia.
Robarts Research Institute.|Graduate Program in Neuroscience.
Benjamin
B
Kolisnyk
Robarts Research Institute.|Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A5K8.
Mohammed
M
Al-Onaizi
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Lilach
L
Soreq
The Edmond and Lily Safra Center for Brain Science and The Silberman Institute of Life Sciences, The Edmond J Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Shahar
S
Barbash
The Edmond and Lily Safra Center for Brain Science and The Silberman Institute of Life Sciences, The Edmond J Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Uriya
U
Bekenstein
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Nejc
N
Haberman
The Edmond and Lily Safra Center for Brain Science and The Silberman Institute of Life Sciences, The Edmond J Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Geula
G
Hanin
Robarts Research Institute.|Department of Physiology and Pharmacology.
Maxine T
MT
Kish
Robarts Research Institute.
Jussemara
J
Souza da Silva
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, CanadaL8S 4K1.
Margaret
M
Fahnestock
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Jernej
J
Ule
The Edmond and Lily Safra Center for Brain Science and The Silberman Institute of Life Sciences, The Edmond J Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Hermona
H
Soreq
Robarts Research Institute.|Graduate Program in Neuroscience.|Department of Physiology and Pharmacology.|Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A5K8.
Vania F
VF
Prado
Robarts Research Institute.|Graduate Program in Neuroscience.|Department of Physiology and Pharmacology.|Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A5K8.
Marco A M
MAM
Prado
D000109:Acetylcholine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007859:Learning Disabilities / Q000209:etiology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D000074482:Thyroid Nuclear Factor 1 / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D050494:Vesicular Acetylcholine Transport Proteins / Q000172:deficiency* / Q000235:genetics
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; C000614414:Nkx2-1 protein, mouse; C493460:Slc18a3 protein, mouse; D013844:Thiazoles; D000074482:Thyroid Nuclear Factor 1; D050494:Vesicular Acetylcholine Transport Proteins; D012313:RNA; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D000109:Acetylcholine
Alzheimer's disease; RNA metabolism; acetylcholine; cognition; pathology