The Aß(1-38) peptide is a negative regulator of the Aß(1-42) peptide implicated in Alzheimer disease progression.

The pool of s-Amyloid (As) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for As peptides. We examined how a naturally occurring variant, e.g. As(1-38), interacts with the AD-related variant, As(1-42), and the predominant physiological variant, As(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that As(1-38) interacts differently with As(1-40) and As(1-42) and, in general, As(1-38) interferes with the conversion of As(1-42) to a s-sheet-rich aggregate. Functionally, As(1-38) reverses the negative impact of As(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an As(1-42) phenotype in Caenorhabditis elegans. As(1-38) also reverses any loss of MTT conversion induced by As(1-40) and As(1-42) in HT-22 hippocampal neurons and APOE Iµ4-positive human fibroblasts, although the combination of As(1-38) and As(1-42) inhibits MTT conversion in APOE Iµ4-negative fibroblasts. A greater ratio of soluble As(1-42)/As(1-38) [and As(1-42)/As(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that As(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant As(1-42).