Depletion of bleomycin hydrolase (Blmh) downregulates histone demethylase Phf8, impairs mTOR signaling/autophagy, accelerates amyloid beta accumulation, and induces neurological deficits in mice

Abstract

Bleomycin hydrolase (BLMH), a homocysteine (Hcy)-thiolactone detoxifying enzyme, is attenuated in brains of Alzheimer’s disease patients. In mice, Blmh depletion causes astrogliosis and behavioral changes. Depletion of histone demethylase PHF8, which controls mTOR signaling by demethylating H4K20me1, causes neuropathy in humans and mice. Here we examined how Blmh depletion affects the Phf8/H4K20me1/mTOR signaling/autophagy pathway and amyloid beta (Aβ) accumulation and cognitive/neuromotor performance in mice. We found that Phf8 was significantly downregulated in brains of Blmh-/- mice vs. Blmh+/+ sibling controls. H4K20me1, mTOR, phospho-mTOR, and App were upregulated while autophagy markers Bcln1, Atg5, and Atg7 were downregulated in Blmh-/- brains. Blmh depletion caused similar biochemical changes and significantly elevated Aβ in Blmh-/-5xFAD vs. Blmh+/+5xFAD brains. Behavioral testing identified cognitive/neuromotor deficits in Blmh-/- and Blmh-/- 5xFAD mice. In Blmh-depleted N2a-APPswe cells, Phf8 was downregulated, while APP, total H4K20me1, and H4K20me1-mTOR promoter binding were elevated.