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Long term worsening of amyloid pathology, cerebral function, and cognition after a single inoculation of beta-amyloid seeds with Osaka mutation

Summary

Researchers found that a single exposure to mutated amyloid-beta proteins (Aβ Osaka) in the brains of genetically modified mice caused lasting damage over four months. The mutated proteins triggered more severe memory loss, brain connectivity problems, and synapse damage compared to normal amyloid-beta. This suggests that even one encounter with mutated amyloid proteins can set off a chain reaction of disease progression that persists long after initial exposure.

Background

Alzheimer’s disease is characterized by accumulation of amyloid-β peptides that induce synaptic dysfunction and cognitive decline. The Aβ Osaka mutation (E693Δ) is associated with familial Alzheimer’s disease and produces Aβ peptides with different structural properties compared to wild-type Aβ. Understanding how mutated Aβ seeds affect disease progression is important for comprehending sporadic pathological events in AD.

Objective

To investigate whether a single intracerebral inoculation of Aβ Osaka mutant peptides can worsen Alzheimer’s disease pathology and impair cognition, cerebral connectivity, and synaptic health several months after exposure in transgenic mice.

Results

Aβ Osaka inoculation induced significant cognitive impairments and reduced hippocampal connectivity compared to controls at 4 months post-inoculation. It increased amyloid plaque deposition and oligomer formation, with more severe synaptic spine loss in neurons exposed to Aβ Osaka compared to wild-type Aβ. Functional connectivity was reduced between the hippocampus and multiple brain regions including the entorhinal cortex and amygdala.

Conclusion

A single exposure to Aβ Osaka seeds triggers a prolonged cascade of pathological events lasting several months, worsening amyloid pathology, synaptic health, and cognitive function in transgenic mice. This demonstrates that sporadic inoculation of mutated amyloid-β can have long-lasting detrimental effects on brain function and disease progression.
  • Published in:Acta Neuropathologica Communications,
  • Study Type:Experimental Animal Study,
  • Source: PMID: 37087498, DOI: 10.1186/s40478-023-01559-0
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