The Pathogenic Ab43 Is Enriched in Familial and Sporadic Alzheimer Disease

The amyloid-cascade hypothesis posits that the role of amyloid b-peptide (Ab) 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 Ab are produced, of which the 40 and 42 residue variants (Ab40 and Ab42) are the most common. Ab42 has a strong tendency to form neurotoxic aggregates and is involved in AD pathogenesis. Longer Ab isoforms, like the less studied Ab43, are gaining attention for their higher propensity to aggregate into neurotoxic oligomers. To further investigate Ab43 in AD, we conducted a quantitative study on Ab43 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 Ab43, as well as Ab40 and Ab42, were quantified using ELISA. We compared quantitative data showing Ab levels in occipital and frontal cortex from sporadic (SAD) and familial (FAD) AD cases, as well as non-demented (ND) controls. Results showed Ab43 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. Ab42 and Ab43 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 Ab43 in human brain are low compared to Ab40 and Ab42, we suggest that Ab43 coul