Abstract Details

To identify compounds endogenous to the human brain capable of curatively inhibiting progression of Alzheimer’s disease (AD).  Although administration of replacement compounds (insulin for diabetes) or analogs of endogenous compounds (isoproterenol as a norepinephrine analog) are time-honored therapeutic strategies, this direction has not been evaluated for AD.  An “endogenous anti-AD compound” represents an unexplored concept.    

AD arises from cytotoxic protein misfolding and aggregation of β-amyloid and tau, concomitantly associated with microglial activation and synaptotoxic/neurotoxic immuno-inflammation, leading to a combined proteopathic-immunopathic pathogenesis.  Since many peptide sequences are susceptible to aggregation, there is evolutionary pressure to inhibit proteopathic misfolding; the immunopathic cascade associated with such misfolding is likewise subject to endogenous regulation.  Accordingly, it is reasonable to postulate the existence of endogenous human brain molecules capable of interrupting  AD disease progression.

We assembled a library of 1,107 molecules (molecular weight<600 Da) endogenous to the human brain and employed a primary in vitro screening assay targeting β-amyloid and tau oligomerization, and then a secondary screen against lipopolysaccharide-triggered, microglial-mediated pro-inflammatory cytokine release.   

The primary screen identified multiple metabolites of tryptophan (indoleamines, anthranilates) as putative endogenous anti-proteopathic agents.  Tryptamine, 5-hydroxytryptamine (5-HT), 5-methoxytryptamine, 3-hydroxyanthranilic acid (3-HA) and nicotinate inhibited β-amyloid and tau aggregation; neither tryptophan nor nicotinamide had any effect.  Beyond anti-aggregation activities, 3-HA reduced glial cytokine expression and cytokine-induced neuronal death while 5-HT inhibited TNF-alpha release from activated microglia – suggesting the capacity of tryptophan metabolites to modulate both parallel pathways of the interdependent proteopathic-immunopathic etiopathogenesis of AD.

We have identified multiple tryptophan metabolites as putative endogenous anti-AD molecules capable of inhibiting AD’s proteopathic-immunopathic cycle.  These results are compatible with clinical data: serum tryptophan levels show a statistically significant reduction with age; people with AD have significantly reduced plasma levels of tryptophan; and, acute tryptophan depletion in people with AD causes increased cognitive dysfunction.