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Age-associated changes in amyloid-β and formaldehyde concentrations in cerebrospinal fluid of rhesus monkeys.

ABSTRACT: Rhesus monkeys ( Macaca mulatta) are valuable experimental animals for studies on neurodegenerative diseases due to their evolutionarily close relationship to humans (Zhang et al., 2014). Rhesus monkeys also display similar hallmarks of aging and neurodegeneration as humans, including formation of senile plaques in the brain (Beckman et al., 2019; Paspalas et al., 2018). However, changes in formaldehyde (FA) levels in the cerebrospinal fluid (CSF) of rhesus monkeys with aging have not been reported. Additionally, whether changes in CSF FA are correlated with changes in amyloid-β (Aβ) concentrations have not yet been explored. Here, the CSF levels of Aβ ₄₀, Aβ ₄₂, and FA were measured in 56 rhesus monkeys of different ages, ranging from 4 to 26 years old. Results revealed significant declines in Aβ ₄₀ and Aβ ₄₂, and an increase in FA with age. Interestingly, the increase in FA levels was negatively correlated with Aβ ₄₀ and Aβ ₄₂ concentrations in aged rhesus monkeys but not in young and middle-aged monkeys. These results appear to parallel changes seen within human aging, i.e., decreased levels of CSF Aβ and increased levels of FA in normal aged adults and Alzheimer's disease (AD) patients. These findings further indicate that rhesus monkeys are a reliable model for studying age-related neurological disorders such as AD and suggest that FA is an important factor in AD development and may be used as a diagnostic indicator of such disease.

SUBMITTER: Li ZH

PROVIDER: S-EPMC7340526 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid ?42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid ?42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.

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Age-associated changes in amyloid-β and formaldehyde concentrations in cerebrospinal fluid of rhesus monkeys.

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