The Pathogenic Aβ43 Is Enriched in Familial and Sporadic Alzheimer Disease

The amyloid-cascade hypothesis posits that the role of amyloid beta-peptide (A beta) in Alzheimer disease (AD) involves polymerization into structures that eventually are deposited as amyloid plaques. During this process, neurotoxic oligomers are formed that induce synaptic loss and neuronal death. Several different isoforms of A beta are produced, of which the 40 and 42 residue variants (A beta 40 and A beta 42) are the most common. A beta 42 has a strong tendency to form neurotoxic aggregates and is involved in AD pathogenesis. Longer A beta isoforms, like the less studied A beta 43, are gaining attention for their higher propensity to aggregate into neurotoxic oligomers. To further investigate A beta 43 in AD, we conducted a quantitative study on A beta 43 levels in human brain. We homogenized human brain tissue and prepared fractions of various solubility; tris buffered saline (TBS), sodium dodecyl sulfate (SDS) and formic acid (FA). Levels of A beta 43, as well as A beta 40 and A beta 42, were quantified using ELISA. We compared quantitative data showing A beta levels in occipital and frontal cortex from sporadic (SAD) and familial (FAD) AD cases, as well as non-demented (ND) controls. Results showed A beta 43 present in each fraction from the SAD and FAD cases, while its level was lower than the detection limit in the majority of the ND-cases. A beta 42 and A beta 43 were enriched in the less soluble fractions (SDS and FA) of SAD and FAD cases in both occipital and frontal cortex. Thus, although the total levels of A beta 43 in human brain are low compared to A beta 40 and A beta 42, we suggest that A beta 43 could initiate the formation of oligomers and amyloid plaques and thereby be crucial to AD pathogenesis.