The Analysis Of Growth And Structures Of Fragmented Aβ Peptides In The Formation Of Aβ Plaques As Spherulites

AmyloidβPeptide（Aβ）is a crucial protein in the pathology of Alzheimer’s Disease（AD）,and the deposition of Aβplaques causes various neurological diseases.Aβis produced by cleavage of Amyloid Precursor Protein（APP）,in which the process results in a series of Aβof different lengths due toγ-secretase cleavage,with different Aβsequences having different physical properties.For example,regions17-21 and 30-35 play a crucial role in the generation and development of AD and may lead to fiber polymorphisms.Also,several point mutations in these two regions have been associated with multiple familial Alzheimer’s diseases.To date,human understanding of Aβaggregation and specific structural domains of AD pathology remains very limited.Therefore,studying Aβfragments is significant for understanding the aggregation functions of different amino acid structural domains.In this thesis,the following two works were carried out on the critical scientific questions in the study of Aβfragments as proposed above:（1）To investigate the differences in the properties of Aβplaques of different fragments,we designed six Aβfragments and achieved the growth of Aβspherulites in vitro.It was found that Aβsequences rich in hydrophilic regions formed spherulites with larger fiber size,while Aβspherulites containing C-terminal and central hydrophobic regions had significantly shorter nucleation time.Using Mueller matrix microscope,we found that the shorter the sequence,the greater the birefringence of the spherulites and the more disordered the fiber arrangement.The central hydrophobic region L¹⁷VFFA²¹ was revealed to be an essential region driving the disorder in the center and edge of Aβplaque by nano-infrared technique,and the C-terminal hydrophobic region A³⁰IIGLMVGGVV⁴⁰ played a key role in the fiber disorder inside Aβplaque.Meanwhile,hydrophobicity Aβspherulites are anti-parallelβ-sheet structures driven by hydrophobic interaction,and hydrophilicity Aβspherulites are mostly parallelβ-sheet and intrafibrillarβ-sheet structures stabilized by salt bridges.（2）To explore the effect of site mutations on the nature of Aβplaque,we designed hydrophobic site-mutated and disease-mutated Aβfragments.We found that the disease mutations at sites 22 and 23 reduced the shape regularity of Aβspherulites,and the overall disorder of fiber arrangement was enhanced in hydrophobic site-mutated Aβspherulites.Furthermore,the results showed that the central region of the Aβspherulites was more orderly due to the mutation of hydrophobic sites,and the internal structure was changed from mainly parallel and anti-parallelβ-sheet to the internalβ-sheet,and the internal fiber disorder was enhanced.The edge structure of the two sequences showed a trend of weakening and strengthening disorder,respectively.