Why do anti-amyloid beta antibodies not work? Time to reconceptualize dementia pathophysiology by incorporating astrocyte melatonergic pathway desynchronization from amyloid-beta production
George Anderson
Abstract
Recent work has challenged the classical, long-standing conceptualization of Alzheimer's disease pathophysiology as driven by amyloid-β plaques and hyperphosphorylated tau tangles, including the treatments thereby derived. This article highlights the importance of the lost synchronization of Nuclear factor kappa B (NF-κB) and yin yang 1 (YY1) induction of β-site amyloid precursor proteincleaving enzyme (BACE)1 induction and amyloid-β production with the melatonergic pathway. Emphasis is placed on the importance of released glia melatonin and autocrine effects in limiting the duration of amyloid-β production and paracrine melatonin's anti-inflammatory effects in neurons, including the suppression of hyperphosphorylated tau. Many of the broader bodies of data on dementia pathophysiology, including the role of the gut microbiome, gut permeability and inflammation, are intimately linked to the regulation of tryptophan's conversion to melatonin and the factors regulating this, including 14-3-3 isoforms, tryptophan hydroxylase (TPH)2, acetyl-CoA, sirtuin-3 and circadian, pineal melatonin. The glia melatonergic pathway is intimately linked to mitochondrial function, from where most melatonin is derived, and provides an important hub to better link wider dementia pathophysiology as well as providing novel treatment targets, challenging the treatment limitations imposed by anti-amyloid antibody treatments. This also has relevance for wider neurodegenerative and neuro-psychiatric conditions.