The Role of Novel Risk Factor IQCK and its Potential Mechanism in the Pathogenesis of Alzheimer’s Disease
Abstract
Introduction and Objective. Alzheimer's disease (AD) is a complex and highly heterogeneous neurological disorder that results in gradual neuronal loss and a decline in cognitive function. Therapeutics targeting amyloid pathology in AD patients have failed so far, indicating that the pathogenesis of AD still needs to be understood thoroughly. Genome-wide association studies (GWAS) have identified several novel AD risk loci. Among these loci, IQ-motif-containing protein K (IQCK), a relatively unexplored gene, has emerged as a potential risk factor for AD. The greatest challenge for future therapeutics is characterizing how these novel risk genes cause AD. Methods. To explore the role of novel risk factor IQCK in AD, we used various cell models including iPSC-derived neurons from normal control and AD patient fibroblasts, primary neurons, synaptosomes, newly generated IQCK transgenic mice, as well as lenti and adenoviruses. We used proteomic analysis, immunoblots, immunocytochemistry, and immunohistochemistry to identify potential mechanisms. Results. Antibody-based microarray screening of 8000 proteins revealed IQCK significantly reduces amyloid precursor-like protein 1 (APLP1) and postsynaptic density protein 95 (PSD-95). These results were validated in several cell lines and, most importantly, in vivo in the IQCK transgenic mice using brain homogenates and synaptosomes as well as immunocytochemistry in the primary neurons derived from IQCK transgenic mice. Both APLP1 and PSD-95 are known to play a pivotal role in the maintenance of dendritic spines, NMDA, and AMPA receptor-based signaling, as well as long-term potentiation and cognition. Interestingly, PSD-95 is mutated in schizophrenia and autism, which are believed to result from disrupted synapses. PSD-95 is also disrupted in intellectual disability, a cognitive and mental disorder characterized by a reduction of dendritic spines. Therefore, IQCK-mediated PSD-95 deficiencies could be attributed to the loss of spines and cognitive impairments associated with AD. Conclusions-Implications. Understanding the role of IQCK in the loss of synaptic integrity in AD pathogenesis could provide valuable insights into the underlying mechanisms of AD and thus may offer novel therapeutic targets. Further research is needed to elucidate the precise mechanism by which IQCK contributes to the loss of synaptic integrity.
Keywords
Aging, IQCK, Alzheimer’s Disease, iPSC neurons
Presentation Type
Poster Presentation
The Role of Novel Risk Factor IQCK and its Potential Mechanism in the Pathogenesis of Alzheimer’s Disease
Introduction and Objective. Alzheimer's disease (AD) is a complex and highly heterogeneous neurological disorder that results in gradual neuronal loss and a decline in cognitive function. Therapeutics targeting amyloid pathology in AD patients have failed so far, indicating that the pathogenesis of AD still needs to be understood thoroughly. Genome-wide association studies (GWAS) have identified several novel AD risk loci. Among these loci, IQ-motif-containing protein K (IQCK), a relatively unexplored gene, has emerged as a potential risk factor for AD. The greatest challenge for future therapeutics is characterizing how these novel risk genes cause AD. Methods. To explore the role of novel risk factor IQCK in AD, we used various cell models including iPSC-derived neurons from normal control and AD patient fibroblasts, primary neurons, synaptosomes, newly generated IQCK transgenic mice, as well as lenti and adenoviruses. We used proteomic analysis, immunoblots, immunocytochemistry, and immunohistochemistry to identify potential mechanisms. Results. Antibody-based microarray screening of 8000 proteins revealed IQCK significantly reduces amyloid precursor-like protein 1 (APLP1) and postsynaptic density protein 95 (PSD-95). These results were validated in several cell lines and, most importantly, in vivo in the IQCK transgenic mice using brain homogenates and synaptosomes as well as immunocytochemistry in the primary neurons derived from IQCK transgenic mice. Both APLP1 and PSD-95 are known to play a pivotal role in the maintenance of dendritic spines, NMDA, and AMPA receptor-based signaling, as well as long-term potentiation and cognition. Interestingly, PSD-95 is mutated in schizophrenia and autism, which are believed to result from disrupted synapses. PSD-95 is also disrupted in intellectual disability, a cognitive and mental disorder characterized by a reduction of dendritic spines. Therefore, IQCK-mediated PSD-95 deficiencies could be attributed to the loss of spines and cognitive impairments associated with AD. Conclusions-Implications. Understanding the role of IQCK in the loss of synaptic integrity in AD pathogenesis could provide valuable insights into the underlying mechanisms of AD and thus may offer novel therapeutic targets. Further research is needed to elucidate the precise mechanism by which IQCK contributes to the loss of synaptic integrity.