Aβ and Tau Prions Causing Alzheimer's Disease

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Alzheimer's disease (AD) is characterized by the presence of both amyloid-beta (Aβ) and tau prions.
• AD is considered a double-prion disease, with misfolded Aβ and tau proteins forming prions.
• The correlation between insoluble Aβ and AD progression is unclear, making it difficult to distinguish between inert amyloids and Aβ prions.

Purpose of the Study:

• To investigate the role of Aβ and tau prions in Alzheimer's disease progression and longevity.
• To develop rapid bioassays for measuring isoform-specific Aβ prions in human and mouse samples.
• To explore the relationship between prion levels, patient longevity, and neuropathology.

Main Methods:

• Utilized cellular bioassays to detect and quantify Aβ and tau prions in postmortem human brain samples and transgenic mouse models.
• Developed rapid bioassays to measure isoform-specific Aβ prion abundance.
• Analyzed correlations between prion levels, patient age at death, sex, genetic background, and neuropathological findings.

Main Results:

• Both Aβ and tau proteins misfold into prions in AD patients.
• Longevity in AD patients correlated inversely with levels of both Aβ and tau prions.
• Tau prion levels decreased exponentially with age at death, despite increasing total insoluble tau, and correlated with phosphorylated tau (p-tau).

Conclusions:

• AD is a double-prion disease where lower prion burden is associated with greater longevity.
• The findings suggest an inverse correlation between neurotoxic tau prions and longevity in AD patients.
• This discovery may inform patient stratification for clinical trials and the development of novel AD therapeutics.