Do anti-amyloid beta protein antibody cross reactivities confound Alzheimer disease research?

ABSTRACT

BACKGROUND: Alzheimer disease (AD) research has focussed mainly on the amyloid beta protein (Aß). However, many Aß-and P3-type peptides derived from the amyloid precursor protein (APP) and peptides thought to derive from Aß catabolism share sequence homology. Additionally, conformations can change dependent on aggregation state and solubility leading to significant uncertainty relating to interpretations of immunoreactivity with antibodies raised against Aß. We review evidence relating to the reactivities of commonly used antibodies including 6F3D, 6E10 and 4G8 and evaluate their reactivity profiles with respect to AD diagnosis and research. RESULTS: Antibody cross-reactivities between Aß-type, P3-type and Aß-catabolic peptides confound interpretations of immunoreactivity. More than one antibody is required to adequately characterise Aß. The relationships between anti-Aß immunoreactivity, neuropathology and proposed APP cleavages are unclear. CONCLUSIONS: We find that the concept of Aß lacks clarity as a specific entity. Anti-Aß antibody cross-reactivities lead to significant uncertainty in our understanding of the APP proteolytic system and its role in AD with profound implications for current research and therapeutic strategies.