Lehrer S and Rheinstein PH (2020), Alignment of Alzheimer's disease amyloid β-pept...

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World Acad Sci J 2020 Jan 01;26:. doi: 10.3892/wasj.2020.68.

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Alignment of Alzheimer's disease amyloid β-peptide and klotho.

Lehrer S , Rheinstein PH .

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The cause of Alzheimer's disease (AD) is poorly understood. In 1991, the amyloid hypothesis postulated that β-amyloid (Aβ) accumulation is a key element. It follows that clearing the brain of Aβ would be beneficial, which has not been the case. Therefore, Aβ is likely a result, not a cause, of AD and may be protective rather than harmful. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for AD. Klotho (KL), encoded by the KL gene, may be another AD-related protein. FGF21 is a circulating endocrine hormone, mainly secreted by the liver, mostly during fasting. FGF21 acts by binding to its receptor FGFR1 and co-receptor β-klotho. FGF21 is neuroprotective and could delay onset of AD. In the present study, the KL protein structure was examined to determine whether it may interact with Aβ. Protein data bank (pdb) entries for klotho and Aβ were searched on the RCSB Protein Data Bank for β-KL and AD amyloid β-peptide. The protein structures were superimposed and aligned on PYMOL v2.3.4 with the super command, which super aligns two protein selections. To evaluate the conservation and alignment of the Aβ and KL genomes across species, BLAT, the Blast-Like Alignment Tool of the UCSC Genome Browser, was used. The amino acid residues phe76-val96 of KL aligned closely with residues asp7-asn27 of Aβ. Cross-species comparison of KL revealed a high degree of alignment and conservation in the chimp and 27 other primates; however, less alignment and conservation were observed in the mouse, dog and elephant, even less in the chicken, western clawed frog (Xenopus tropicalis), zebrafish and lamprey. The current finding of amino acid residues phe76-val96 of klotho aligning closely with residues asp7-asn27 of Aβ suggests that Aβ can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD. The problem arises with age. Older individuals do not heal or repair tissue damage as well as younger individuals. As neurodegeneration advances in an older individual, perhaps caused by neuroinflammation related to herpes simplex virus type 1, increasing amounts of amyloid are produced, forming an adhesive web, as the brain tries to hold the pathologic process in check. Meanwhile, the damage increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.

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Species referenced: Xenopus tropicalis
Genes referenced: fgfr1 kl

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References [+] :

Belloy, Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4. 2020, Pubmed

	Figure 2. Solution structure of the Alzheimerâs disease AÎ²-peptide.
	Figure 3. Alignment of klotho peptide (green) domain 1 (D1) with AÎ² (blue). FGF21 (red) is bound to domain 1.
	Figure 4. Closeup of alignment. Pymol performed 6 cycles of calculations on 165 aligned atoms, with a final root mean square deviation of atomic positions (RMSD) of 1.792 Ã for 148 atoms. Amino acid residues phe76-val96 of klotho aligned closely with residues asp7-asn27 of AÎ².
	Figure 5. Alignment of 42 amino acid residue human AÎ² across species in the UCSC genome browser. There is a high degree of alignment and conservation of AÎ² (chr 21q21.3) in the rhesus monkey and 27 other primates, but much less alignment and conservation in the mouse, dog, and elephant, even less in the chicken, western clawed frog (Xenopus tropicalis), zebrafish and lamprey.
	Figure 6. Alignment of human klotho across species in the UCSC genome browser. Results of the cross-species comparison of klotho show a high degree of alignment and conservation of human klotho (chr 13q13.1) in the chimp and 27 other primates, less alignment and conservation in the mouse, dog, and elephant, even less in the chicken, western clawed frog (Xenopus tropicalis), zebrafish and lamprey.