Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice

Abstract

Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in the brains of patients with Alzheimer disease (AD). Here, we tested whether the experimental agent methylene blue (MB), used for treatment of methemoglobinemia, might improve AD-like pathology and behavioral deficits. We orally administered MB to the aged transgenic PSAPP mouse model of cerebral amyloidosis and evaluated cognitive function and cerebral amyloid pathology. Beginning at 15 months of age, animals were gavaged with MB (3 mg/kg) or vehicle once daily for 3 months. MB treatment significantly prevented transgene-associated behavioral impairment, including hyperactivity, decreased object recognition, and defective spatial working and reference memory, but it did not alter nontransgenic mouse behavior. Moreover, brain parenchymal and cerebral vascular β-amyloid deposits as well as levels of various Aβ species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, β-carboxyl-terminal APP fragment and β-site APP cleaving enzyme 1 protein expression and activity were attenuated. Additionally, treatment of Chinese hamster ovary cells overexpressing human wild-type APP with MB significantly decreased Aβ production and amyloidogenic APP proteolysis. These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway.

Inhibition of protein aggregation and amyloid formation by small molecules

“…Alzhemed was stopped after human trials and Methylene Blue variants [13 ] are undergoing human trials. 2 with one N-methylated residue, inhibits Ab aggregation and toxicity.…”

A Bird’s-Eye View of the Multiple Biochemical Mechanisms that Propel Pathology of Alzheimer’s Disease: Recent Advances and Mechanistic Perspectives on How to Halt the Disease Progression Targeting Multiple Pathways

“…Callaway et al [125] showed that the assistance provided by MB during oxidative phosphorylation was able to improve memory retention in rats. MB has also been shown to prevent oligomerization of A␤ as well as its extracellular accumulation forcing aggregates to go through nucleate fibril formation [126,127]. This is done by targeting beta secretase-1 (BACE1) reducing its stability and reduces ␤-secretase activity which decreases the number of A␤ species [127].…”

Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery

“…28 MB also reduced soluble Aβ and rescued early cognitive deficit in AD transgenic mice. 29 In HD, MB can slow down the aggregation of mHTT protein even when aggregation has already been initiated, and aggregated species were presented in vitro . 8 In primary neurons expressing mHTT, MB reduced the formation of both oligomeric and insoluble mHTT and increased the survival of neurons.…”