title: The human-specific CASP4 gene product contributes to Alzheimer-related synaptic and behavioural deficits.
abstract: Recent studies have indicated that innate immune signalling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Aβ) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is an important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mice manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the aetiology of AD, we have now analysed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice. We observed that the expression of caspase-4 was strongly correlated with AD risk genes including TYROBP, TREM2, CR1, PSEN1, MS4A4A and MS4A6A in LOAD brains. Caspase-4 expression was upregulated in CASP4/APP/PS1 mice in a region-specific manner, including hippocampus and prefrontal cortex. In APP/PS1 mice, caspase-4 expression led to impairments in the reversal phase of a Barnes maze task and in hippocampal synaptic plasticity, without affecting soluble or aggregated Aβ levels. Caspase-4 was expressed predominantly in microglial cells, and in the presence of CASP4, more microglia were clustered around amyloid plaques. Furthermore, our data indicated that caspase-4 modulates microglial cells in a manner that increases proinflammatory processes. We propose that microglial caspase-4 expression contributes to the cognitive impairments in AD, and that further study of caspase-4 will enhance our understanding of AD pathogenesis and may lead to novel therapeutic targets in AD.
authors: Department of Psychiatry.
authors: Yuji
authors: Y
authors: Kajiwara
authors: Department of Genetics and Genomic Sciences.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY, USA.
authors: Andrew
authors: A
authors: McKenzie
authors: General Medical Research Service.
authors: Nate
authors: N
authors: Dorr
authors: Department of Psychiatry.|General Medical Research Service.
authors: Miguel A
authors: MA
authors: Gama Sosa
authors: Department of Psychiatry.|Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, USA.|Department of Neurology.
authors: Gregory
authors: G
authors: Elder
authors: Department of Psychiatry.
authors: James
authors: J
authors: Schmeidler
authors: Department of Neuroscience.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Dara L
authors: DL
authors: Dickstein
authors: Department of Psychiatry.
authors: Ozlem
authors: O
authors: Bozdagi
authors: Department of Genetics and Genomic Sciences.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY, USA.
authors: Bin
authors: B
authors: Zhang
authors: Department of Psychiatry Joseph.Buxbaum@mssm.edu.|Department of Genetics and Genomic Sciences.|Department of Neuroscience.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Joseph D
authors: JD
authors: Buxbaum
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D053471:Caspases, Initiator / Q000096:biosynthesis / Q000235:genetics*; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009473:Neuronal Plasticity / Q000235:genetics; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; C580804:presenilin 1, mouse; C093516:CASP4 protein, human; D053471:Caspases, Initiator