Lactate supplement for treatment of dementia & depression

Offentlig prosjektsammendrag

Age-associated cognitive impairments such as Alzheimer’s disease (AD) are becoming the major health problem worldwide, increasing as the proportion of old age individuals increases. There is no disease-modifying or other effective treatment available. AD is characterized by the progressive accumulation of ß-amyloid peptides (Aß), first in neurons, and later extracellularly as amyloid plaques. In addition, there are deposits of intraneuronal phosphorylated tau proteins, as well as neuronal loss. The necessity of a novel approach to treat AD is underlined by the lack of success of treatment strategies directed against amyloid plaques and neurofibrillary tangles. This calls for alternative strategies. Physical exercise significantly reduces the risk of developing AD (eg, Scarmeas N et al 2011 Am J Geriatr Psychiatry), delays functional deterioration in AD patients (Pitkälä KH 2013 JAMA Intern Med), and counteracts cognitive decline in old age also independent of AD (Hayes SM et al 2016 J Gerontol B Psychol Sci Soc Sci). In mouse models of AD, physical activity arrests cognitive impairment and stops progression of brain AD pathology (eg, Hüttenrauch M et al 2016 Transl Psychiatry). However, how exercise brings about these changes has been unclear. Lactate increases dramatically in intense exercise, to levels that stimulate the lactate receptor HCAR1, which we discovered to be present and active in brain, downregulating the signaling molecule cAMP (Lauritzen KH et al 2014 Cereb Cortex). Lowering of cAMP should help correct age-related increase in cAMP-dependent phosphorylation of tau that causes degeneration in monkey cortex (Carlyle BC et al 2014 PNAS). Activation of HCAR1, acting also through other down-stream mechanisms than cAMP, can block inflammatory tissue damage (Hoque R et al 2014 Gastroenterology; Madaan A et al 2017 Am J Obstet Gynecol) and enhance DNA repair (Wagner W et al 2015 Cell Commun Signal), processes implicated in AD.