Aph1c-KO Mouse

Aph1c is one of the genes encoding subunits of the gamma-secretase complex. Gamma-secretase is crucial for amyloid beta peptide release and is involved in Notch, N-Cadherin, and potentially other signaling pathways [1]. The complex consists of at least four subunits: Presenilin, Aph1 (including Aph1c), Pen2, and Nicastrin.

In mice, Aph1C-/-mice can survive into adulthood. However, combined Aph1BC-/-deficiency causes a mild but significant reduction in amyloid beta precursor protein processing in selective regions of the adult brain, suggesting a role of Aph1c in this process [1]. Also, the rodent-specific Aph1C mRNA is highly expressed in the kidney and testis but not in the brain or other tissues, indicating tissue-specific expression of the gamma-secretase complex component [2]. Additionally, deficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage in the brain and causes pharmacological and behavioral abnormalities relevant to schizophrenia pathogenesis, which can be reversed by antipsychotic drugs [3].

In conclusion, Aph1c is a subunit-encoding gene of the gamma-secretase complex with tissue-specific expression. Gene knockout mouse models, especially those related to Aph1BC deficiency, have revealed its role in amyloid beta precursor protein processing in the brain and Nrg1 cleavage relevant to schizophrenia-like phenotypes. These findings contribute to understanding the biological functions of gamma-secretase in vivo and may provide insights for treating related diseases such as Alzheimer's disease and schizophrenia.

References:

1. Serneels, Lutgarde, Dejaegere, Tim, Craessaerts, Katleen, Hartmann, Dieter, De Strooper, Bart. 2005. Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo. In Proceedings of the National Academy of Sciences of the United States of America, 102, 1719-24. doi:. https://pubmed.ncbi.nlm.nih.gov/15665098/

2. Hébert, Sébastien S, Serneels, Lutgarde, Dejaegere, Tim, Hartmann, Dieter, De Strooper, Bart. . Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity. In Neurobiology of disease, 17, 260-72. doi:. https://pubmed.ncbi.nlm.nih.gov/15474363/

3. Dejaegere, T, Serneels, L, Schäfer, M K, D'Hooge, R, De Strooper, B. 2008. Deficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. In Proceedings of the National Academy of Sciences of the United States of America, 105, 9775-80. doi:10.1073/pnas.0800507105. https://pubmed.ncbi.nlm.nih.gov/18626010/