Brain Amyloid-Beta Fragment Signatures in Pathological Ageing and Alzheimer's Disease by Hybrid Immunoprecipitation Mass Spectrometry

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Background: Senile plaques in Alzheimer's disease (AD) are composed of amyloid-β (Aβ), especially N-truncated forms including Aβ_4-42. These are thought to be neurotoxic. However, individuals may live for decades with biomarker evidence of cerebral β-amyloidosis (positive amyloid PET imaging and/or low cerebrospinal fluid levels of the 42 amino acid form of Aβ) without cognitive impairment. This condition may be termed pathological ageing (PA). Objective: To investigate whether there is a difference in the cerebral Aβ fragment pattern in brain specimens from non-demented (PA) and demented (AD) individuals expressing the full neuropathological triad of AD (senile plaques, neurofibrillary tangles and neurodegeneration). Methods: We extracted Aβ using formic acid and hybrid (6E10 and 4G8) immunoprecipitation from fresh-frozen temporal cortex tissue of 6 elderly individuals (mean age ± SD: 89 ± 3.5 years) with PA and 10 patients with AD (mean age ± SD: 72 ± 8.5 years). The full spectrum of Aβ peptides was determined by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Results: AD patients had generally more N-terminally truncated and pyroglutamate-modified Aβ than PA patients, whereas PA patients had on average more Aβ_1-40 than AD patients. Conclusion: Senile plaques in AD may have an Aβ fragment composition distinct from PA with more N-terminally and pyroglutamate-modified Aβ peptides that may be linked to neurotoxicity.