Polymorphic SERPINA3 prolongs oligomeric state of amyloid beta

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Alzheimer's disease (AD) is characterized by amyloid peptide accumulation.
• The molecular chaperone SERPINA3 has been observed to colocalize with amyloid deposits in AD brains.

Purpose of the Study:

• To investigate the role of SERPINA3, specifically its variants and polymorphisms, in the aggregation and neurotoxicity of amyloid-beta (Aβ) peptides relevant to Alzheimer's disease.

Main Methods:

• Quantitative Trait Locus (QTL) analysis in senescence-accelerated mouse prone (SAMP) 8 strain to identify Serpina3.
• Transmission electron microscopy (TEM) and Western blot analysis to assess Aβ 42 oligomer retention.
• Neuronal cell death assays using SH-SY5Y neuroblastoma cells with different SERPINA3 variants.
• Analysis of SERPINA3 gene polymorphisms (I308T, rs142398813) in the Japanese SNP database for geriatric research (JG-SNP).

Main Results:

• SAMP8-type SERPINA3 prolonged the retention of oligomeric Aβ 42 for up to 72 hours.
• Aβ 42 oligomeric forms (trimers, tetramers) were maintained longer in the presence of SAMP8-type SERPINA3.
• Preincubation of Aβ 42 with SAMP8-type SERPINA3 induced neuronal cell death in SH-SY5Y cells.
• The polymorphic SERPINA3 I308T variant prolonged toxic oligomeric Aβ 42 forms for 48 hours, leading to neuronal cell death.

Conclusions:

• The study elucidates the pathogenic regulatory role of polymorphic SERPINA3 in neurodegeneration.
• Specific variants and polymorphisms of SERPINA3 can enhance the persistence of toxic Aβ 42 oligomers, contributing to neuronal cell death in Alzheimer's disease.