Degradation of FA reduces A[beta] neurotoxicity and Alzheimer-related phenotypes

Dysregulation of formaldehyde (FA) has been implicated in the development of Alzheimer's Disease (AD). Elevated FA levels in Alzheimer's patients and animal models are associated with impaired cognitive functions. However, the exact role of FA in AD remains unknown. We now identified that oxidative demethylation at serine.sup.8/26 of amyloid-beta protein (A[beta]) induced FA generation and FA cross-linked with the lysine.sup.28 residue in the [beta]-turn of A[beta] monomer to form A[beta] dimers, and then accelerated A[beta] oligomerization and fibrillogenesis in vitro. However, A[beta]42 mutation in serine.sup.8/26, lysine.sup.28 abolished A[beta] self-aggregation. Furthermore, A[beta] inhibited the activity of formaldehyde dehydrogenase (FDH), the enzyme for FA degradation, resulting in FA accumulation. In turn, excess of FA stimulated A[beta] aggregation both in vitro and in vivo by increasing the formation of A[beta] oligomers and fibrils. We found that degradation of FA by formaldehyde scavenger-NaHSO.sub.3 or coenzyme Q10 reduced A[beta] aggregation and ameliorated the neurotoxicity, and improved the cognitive performance in APP/PS1 mice. Our study provides evidence that endogenous FA is essential for A[beta] self-aggregation and scavenging FA could be an effective strategy for treating AD.