Alzheimer's Disease-Like Pathologies and Cognitive Impairments Induced by Formaldehyde in Non-Human Primates

BACKGROUND: Formaldehyde (FA) has been implicated in Alzheimer's disease (AD) pathology as an age-related factor and as a protein cross-linker known to aggregate Amyloid-Beta (Aβ) and tau protein in vitro. Higher levels of FA have also been found in patients with greater cognitive impairment and in AD patient brains. OBJECTIVE: To directly evaluate the effect of chronically elevated FA levels on the primate brain with respect to AD pathological markers. METHOD: Young rhesus macaques (5-8 yrs, without AD related mutations) were given chronic intracerebroventricular (i.c.v.) injections of FA or vehicle over a 12-month period. Monkeys were monitored for changes in cognitive ability and evaluated post-mortem for common AD pathological markers. RESULTS: Monkeys injected with FA were found to have significant spatial working memory impairments. Histopathological analysis revealed the presence of amyloid-β+ neuritic-like plaques, neurofibrillary tangle-like formations, increased tau protein phosphorylation, neuronal loss and reactive gliosis in three memory (and AD) related brain areas (the hippocampus, entorhinal cortex and prefrontal cortex (PFC)) of monkeys receiving i.c.v. injections of FA. ELISA assays revealed that the amounts of pT181 and Aβ42 were markedly higher in the PFC and hippocampus of FA treated monkeys. CONCLUSION: FA was found to induce major AD-like pathological markers and cognitive impairments in young rhesus monkeys independent of genetic predispositions. This suggests FA may play a significant role in the initiation and progression of the disease.