Nat commun: a β protein synthesized in vitro is different from brain-derived a β protein of Alzheimer's disease in structure

November 17, 2019 / Biovalley BIOON / - -- Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the deposition of a β amyloid fibrils (also known as a β fibrils) and tau protein derived neurofibrillar tangles in neurons Some observations have shown that a β peptide is essential to trigger the onset of disease The abnormal duplication of a β precursor protein (APP) coding gene and mutation of APP gene or enzyme coding gene involved in APP processing can lead to Alzheimer's disease Amyloid angiopathy (CAA) can be caused by a β peptide and its related fibrils A β deposits may contain different primary structural variants of a β peptide The a β peptide variants a β (1-40) and a β (1-42) of 40 and 42 amino acid residues have been studied in depth Although a β (1-42) peptide is thought to be pathogenic through the formation of toxic fibril intermediates, a β (1-40) will form fibril deposits, which will cause damage to the cerebrovascular wall A lot of current knowledge about a β peptide comes from the analysis of a β fibrils and other aggregates, which are formed by a β peptide synthesized or recombined in vitro These a β aggregates from test tubes are usually rich in β - fold layers A β fibrils have cross β structure and affinity for Congo red, similar to amyloid fibrils purified from patient tissues The a β fibrils formed in vitro are highly polymorphic, and a series of different peptide conformations have been found in different forms of a β fibrils formed by different a β peptide variants or under different conditions of fibril formation However, up to now, it is not clear which of these structures or whether any of them correctly reflect the pathogenic structure of a β peptide in the brain In a new study, researchers from the University of Ulm and the University of Tubingen in Germany analyzed the structural morphology of a β amyloid fiber from AD brain tissue They found that brain-derived a β fibrils consist of a variety of fibrillar forms In the case of fibril morphology I, they obtained a structural model to determine a β peptide folding: according to the existence of two identical peptide stacks, right-handed fibrils, false 21 helix symmetry and fibril polarity, the fibrils were assembled in layers The relevant research results were recently published in the Journal of nature communications, with the title of "cryo EM structure and polymerization of a β amino fabrics purified from Alzheimer's brain tissue" Picture from nature communications, 2019, DOI: 10.1038/s41467-019-12683-8 The robustness of this model is confirmed by its corresponding relationship with the 2D class averages and power spectra, the Fourier shell correlation (FSC) value of 4.5 when compared with the 3D spectra, and the ψ / Φ angle distribution which truly reflects the right-handed topological structure of brain-derived fibrils However, there are still uncertainties in the detailed geometry of the main polypeptide chain and amino acid side chain The C-peptide folding observed in this study is novel and different from the previous description of a β structure formed in vitro The unique feature of this fibril structure is that the N-terminal bow structure and the amino acid residues 24-26 are in the central position, which is different from the previous description of a β fibril: amino acid residues 30-42 form the most central structural element The folding of a β peptide in form I is very consistent with the three-dimensional pattern obtained in fibrillar forms II and III Although the three-dimensional map of the latter two forms has lower resolution than that of form I, it is clear that in all three forms of fibrils, the general fibril structure is conservative, and the main difference between them is the number of fibrils These three fibril forms account for the majority of the fibrils visible in the samples used in this study, suggesting that this described structure represents a β amyloid fibril from the patient's brain These three fibrillar forms were consistently found in the fibrillar extracts of all three AD patients analyzed in this study However, it cannot be ruled out that other a β fibrillar forms may also be present in the brain, such as in patients affected by certain a β peptide variants Fourteen mutations have been found in the a β peptide sequence Twelve of these mutations have been reported to promote AD and / or CAA, while ala2thre mutations are protective, and his6arg mutations are of uncertain relevance Most mutations have no significant stabilizing or destabilizing effect on the structure described in this study This observation is consistent with the study of cell biology, which indicates that they may affect the proteolysis of a β peptide Or, some mutations may simply promote aggregation as a whole rather than specific fibrillar morphology There are only three mutations that induce or remove contact, which may destabilize the structure: glu11lys and lys16asn destroy the salt bridge in the N-terminal bow, while leu34val removes the methylene in the C-terminal bow However, the first two mutations were described as acting on the proteolysis of a β, while the second one promoted rather than prevented CAA One particularly interesting structural feature of brain-derived fibrils observed in this study is that they are right-handed This property is strongly different from the previously described left-handed rotation of a β (1 – 40) and a β (1 – 42) fibrils formed in vitro, and more obviously, it is also significantly different from the spherical protein structure with strong preference for the reverse twisted β - folded sheet This new study found a second human pathogenic fibrillar protein related to the in vivo right-handed amyloid fibrils The first is the common serum amyloid a protein variant in human systemic AA amyloidosis Although the molecular origin of this right-handed protein remains to be determined, the distribution of ψ / Φ pairs in the Ramachandran plot of a β and AA amyloid fibrils suggests that the folding of the fibrils induces the right-handed protein Consistent with this view, the a β folding described in this study is basically different from the a β peptide folding observed in the previously described L-A β fibrils These findings highlight the importance of using patient derived amyloid fibrils when studying the structural basis of the disease Before that, the research on several other kinds of fibrillary proteins also reached a similar conclusion: the fibrillar structure they produce in vitro is different from their pathogenic form in human body However, it may be a premature conclusion that the fibrils formed in vitro must be different from those in patients On the contrary, the authors conclude that the differences observed in these specific situations reflect a mismatch between the conditions of fibrillation in vitro and in vivo As a result, they lead to different fibrillar morphology, which is consistent with the view that amyloid structure is determined by the host and specific misfolded proteins Together with some recent studies, the data from this new study support the concept that disease pathology originates from specific fibrillar morphology or fibrillar protein conformation First of all, although it has been confirmed that a β peptide can adopt a variety of morphologically different fibrillar structures through previous studies of a β fibrillation in vitro, this new study shows that the pathology of the disease is only related to the morphology of certain structurally related fibrils These fibrillar forms are always present in the fibrillar extracts of patients presenting the same neuropathological characteristics Similar observations have been reported for other fibrillar systems, including human attr and AA amyloidosis and tau dependent neuropathology Even different mice affected by systemic AA amyloidosis had the same fibrillar morphology Secondly, the recent cryo-EM structure of mouse AA amyloid fibrils provides evidence that the resistance of some mouse strains to systemic AA amyloidosis is not caused by the inability of serum amyloid a protein variants to form cross β fibrils, but by their incompatibility with pathologically related fibrils Third, different variants of the disease can be related to different forms of fibrils Such examples include A-type and B-type amyloid fibrils in hereditary attr amyloidosis, different fibrils in "common" and "vascular" variants in systemic AA amyloidosis, or different tau fibrils in different forms of neurodegeneration As a result of these observations, targeting specific fibrillar morphology with appropriate selective inhibitors may be an attractive strategy for interfering with the disease process This new study provides refined structural information about a β (BIOON Com) reference: Marius Kollmer et al Cryo EM structure and polymers of a β aminoid fabrics purified from Alzheimer's brain tissue Nature communications, 2019, DOI: 10.1038/s41467-019-12683-8