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

Background: Senile plaques in Alzheimer's disease (AD) are composed of amyloid-beta (A beta) especially N-truncated forms including A beta(4-42). These are thought to be neurotoxic. However, individuals may live for decades with biomarker evidence of cerebral beta-amyloidosis (positive amyloid PET imaging and/or low cerebrospinal fluid levels of the 42 amino acid form of A beta) without cognitive impairment. This condition may be termed pathological ageing (PA). Objective: To investigate whether there is a difference in the cerebral A beta 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 A beta 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 A beta 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 A beta than PA patients, whereas PA patients had on average more A beta(1-40) than AD patients. Conclusion: Senile plaques in AD may have an AB fragment composition distinct from PA with more N-terminally and pyroglutamate-modified A beta peptides that may be linked to neurotoxicity. (C) 2015 S. Karger AG, Basel