Alignment of Human Aquaporin 4 and beta-amyloid proteins may indicate involvement of beta-amyloid in prevention of brain edema

Abstract

Abstract Background: Because brain edema has occurred during Alzheimer Disease (AD) clinical trials of most anti-amyloid antibodies, we hypothesize that beta-amyloid might be an important element in brain water homeostasis. Removing beta-amyloid could harm some AD patients. To investigate this idea, we analyzed structures of aquaporin-4 and beta-amyloid from the RCSB protein data bank. Aquaporins, a family of water channel proteins that have been found in animals, may provide an explanation for AD brain edema. Aquaporin-4 (AQP4), the most significant form of aquaporin in the central nervous system, mediates water homeostasis in healthy and pathological settings, such as severe brain injury. APOE isoform affects neurological prognosis following intracerebral hemorrhage. Poor functional outcome and higher cerebral edema are linked to APOE4. Methods: We examined two RCSB Protein Data Bank molecules: 2D57. Double layered 2D crystal structure of Aquaporin-4; Solution structure of the first PDZ domain of beta-amyloid A4 precursor protein-binding family A, member 1. The protein structures were superimposed and aligned on PYMOL v 2.5.0 with the Super command, which super aligns two protein selections. Results: Pymol performed 5 cycles of calculations on 29 aligned atoms of aquaporin-4 and beta-amyloid proteins, with a final root mean square deviation of atomic positions (RMSD) of 0.300 Å for 21 atoms. Lower values of RMSD indicate that alignment is validated with higher accuracy. RMSD values of 1 Å or less indicate very good alignment. The 21-atom alignment is excellent. Conclusion: Alignments are a powerful way to compare related protein sequences. They can be used to record a variety of information about matched sequences, such as shared structural function or common evolutionary ancestry. Our analysis indicates that AQP4 and beta-amyloid may have shared functions, including maintenance of brain water homeostasis and prevention of brain edema. Asymptomatic vasogenic edema has been found in AD patients who have received no treatment at all. Therefore, focal, localized vasogenic edema may be part of the AD pathologic process. We conclude that beta-amyloid may protect against vasogenic brain edema. Removing beta-amyloid from AD patients may promote vasogenic brain edema and bleeding. Screening for AQP4 polymorphisms and APOE4 isoform, as well as ABCC8 polymorphisms and haptoglobin form, could identify patients at high risk of brain edema and hemorrhage before anti-amyloid treatment for AD is begun. The association of APOE4 with brain edema may be one reason for increased AD risk in carriers of APOE4. Further studies are warranted.