Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging

Area of Science:

• Neuroscience
• Aging Research
• Alzheimer's Disease Pathogenesis

Background:

• Aging is the primary risk factor for Alzheimer's disease (AD), yet effective treatments remain elusive.
• A significant translational gap exists, with many drugs failing in clinical trials despite promising results in rodent models.
• Understanding age-related neurobiological changes, particularly those affecting synaptic integrity, is crucial for AD prevention and treatment.

Purpose of the Study:

• To develop a non-human primate model of Alzheimer's disease (AD) that recapitulates key aspects of the human condition.
• To investigate the effects of soluble amyloid beta oligomers (AβOs) on synaptic integrity and neuroinflammation in the aged primate brain.
• To establish a translational platform for testing novel AD therapies.

Main Methods:

• Infusion of soluble amyloid beta oligomers (AβOs) into the prefrontal cortex of rhesus monkeys.
• Assessment of neuroinflammation, AD biomarkers in cerebrospinal fluid (CSF), and dendritic spine morphology.
• Comparison of observed pathologies with those in normal aging and human AD patients.

Main Results:

• AβOs targeted specific dendritic spines in the prefrontal cortex, inducing neuroinflammation.
• Elevated AD biomarkers in CSF were observed, comparable to levels in human AD patients.
• Dendritic spine loss similar to normal aging was detected, without amyloid plaques or tau pathology.

Conclusions:

• The rhesus monkey model effectively replicates key aspects of AD-related synaptic impairment and neuroinflammation.
• This primate model provides a valuable platform for studying age-related brain vulnerabilities and developing disease-modifying therapies for AD.
• Targeting synaptic integrity is a promising strategy for early intervention and prevention of cognitive decline.