Amyloid Alpha: The Neglected Cousin of Amyloid Beta

For decades, amyloid β (Aβ) has been the principal therapeutic target for therapies of Alzheimer's disease (AD). An alternative processing product, known as P3, may form if the amyloid precursor protein is cleaved by α-secretase instead of β-secretase. This shorter peptide has received little attention and is often dismissed as nonamyloidogenic and nontoxic. Our research, and that of others, has shown that the shorter peptide is anything but innocuous. We demonstrated that P3-or Amyloid α (Aα) as we termed it-readily forms oligomers and fibrils and is itself potentially neurotoxic and may interact with Aβ to modulate the aggregation behavior and toxicity of Aβ. This perspective article provides a succinct overview of current uncertainties around P3/Aα. A revision of the amyloid cascade hypothesis to include P3/Aα is urgently needed. This peptide is, most likely, not an innocent bystander, but a distinct aggregating peptide that is itself potentially neurotoxic and may be contributing to AD.