The human-specificCASP4gene 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 (Ab) 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 Ab 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.

TREM2 ectodomain and its soluble form in Alzheimer’s disease

“…By regulating synaptic pruning, sTREM2 may be involved in signal transmission between neurons. Although a deficit of TREM2 may impair synaptic structure [95] and lead to cognitive impairments in an AD mice model [96], it is still unclear how this process occurs in humans.…”

Phenotypic and genotypic characterization of families with complex intellectual disability identified pathogenic genetic variations in known and novel disease genes

“…For cell transfections, HEK293T were maintained in 1X Dubelcco's Modified Eagle's Medium (1x DMEM) (Corning, USA), supplemented with 10% Fetal Bovine Serum (FBS) and 1% Penicillin/Streptomycin (GIBCO, USA), and kept in a 37 °C/5%CO2 incubator. Primary hippocampal neuron cultures were prepared from E15.5 wt C57BL6 mouse embryo as previously described 54 , maintained in neurobasal medium supplemented with B27 and 1% Penicillin/Streptomycin, and kept in a 37 °C/5%CO2 incubator. Both HEK293T cells and hippocampal neurons were plated in 24-well plates with a density around 2*10E05 cells/ml and transfected by using Lipofectamine 3000 (ThemoFisher, USA) according to the manufacturer's instructions.…”

Caspase 4 Overexpression as a Prognostic Marker in Clear Cell Renal Cell Carcinoma: A Study Based on the Cancer Genome Atlas Data Mining

“…In the human genome, the caspase (aspartate-specific cysteinyl proteinase) family contains at least 12 members (including CASP1 , CASP3 , and CASP4 ), which are involved in several important physiological processes, such as apoptosis, growth, necrosis, and inflammation ( Van Opdenbosch and Lamkanfi, 2019 ). Among them, caspase 4 ( CASP4 ) has been associated with many diseases, including inflammatory bowel disease ( Flood et al, 2015 ), Alzheimer’s disease ( Kajiwara et al, 2016 ), Parkinson’s disease ( Arai et al, 2006 ), and various malignancies ( Scapoli et al, 2011 ; Nilsson, 2013 ; Schulten et al, 2016 ; Papoff et al, 2018 ). However, the relationship between the expression of CASP4 and the clinical prognosis of ccRCC patients remains unclear.…”