Amyloid-beta precursor protein p3 fragment (p3)

The p3 peptide is a proteolytic fragment of the Amyloid-beta precursor protein (APP), generated through sequential cleavage by alpha-secretase (such as ADAM10 or ADAM17) and the gamma-secretase complex [1, 5]. Historically, the production of p3 was considered the hallmark of the "non-amyloidogenic" pathway, as alpha-secretase cleaves within the Amyloid-beta (Aβ) sequence, thereby precluding the formation of the full-length, neurotoxic Aβ peptide [2, 6]. However, recent biochemical and biophysical studies have challenged this view, demonstrating that p3 (specifically the Aβ17-40 and Aβ17-42 variants) is highly hydrophobic and capable of self-assembling into toxic oligomers and amyloid fibrils even more rapidly than Aβ [1, 4]. This has led to the proposal of the name "Amyloid-alpha" (Aα) and the suggestion that p3 may be a significant, yet overlooked, contributor to neurodegeneration in Alzheimer's disease and Down syndrome [2, 11]. The peptide is found in preamyloid plaques and has been shown to exhibit cytotoxicity in neuronal cell cultures, potentially through the formation of membrane-disrupting pores [5, 6]. While no drugs are currently approved to target p3 specifically, its emerging status as a neurotoxic species suggests that therapeutic strategies aimed at neutralizing its aggregation or modulating its production may be necessary [1, 2]. Furthermore, the role of p3 is being scrutinized to explain the clinical failure of BACE1 inhibitors, which inadvertently increase p3 levels by shunting APP processing toward the alpha-secretase pathway [1, 5]. Consequently, p3 represents a novel focal point for drug development in the field of neurodegenerative diseases [11].

Other names

Amyloid-alphaAαAβ(17-40)Aβ(17-42)P3 peptide

Neutralization of toxic oligomers or inhibition of peptide aggregation