Tau seeds from Alzheimer's disease brains trigger tau spread in macaques while oligomeric-Aβ mediates pathology
Morgane Darricau1, Changsong Dou2, Remi Kinet1
1Univ. Bordeaux, CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France.
Introduction:
The "prion-like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid-β (Aβ) have never been experimentally studied in primates phylogenetically close to humans.
Methods:
We injected 17 macaques in the entorhinal cortex with nanograms of seeding-competent tau aggregates purified from AD brains or control extracts from aged-matched healthy brains, with or without intracerebroventricular co-injections of oligomeric-Aβ.
Results:
Pathological tau injection increased cerebrospinal fluid (CSF) p-tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD-related molecular networks were impacted by tau seeds injections regardless of Aβ injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total-tau concentration, and pre- and postsynaptic degeneration only in Aβ co-injected macaques.
Discussion:
Oligomeric-Aβ mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading.
Highlights:
This study supports the "prion-like" properties of misfolded tau extracted from AD brains. This study empirically validates the Braak staging in an anthropomorphic brain. This study highlights the role of oligomeric Aβ in driving the maturation and toxicity of tau pathology. This work establishes a novel animal model of early sporadic AD that is closer to the human pathology.
Insights
Alzheimer's disease (AD) tau pathology spreads like a prion in macaques. Amyloid-beta (Aβ) accelerates tau maturation and toxicity, creating a new model for AD research.
Area of Science:
- Neuroscience
- Pathology
- Prion Biology
Background:
- Alzheimer's disease (AD) is characterized by tauopathy and amyloid-beta (Aβ) plaques.
- The prion-like spread of tau pathology and the role of Aβ have not been studied in primates.
- Primate models are crucial for understanding human neurodegenerative diseases.
Purpose of the Study:
- To investigate the prion-like spread of tau pathology in macaques.
- To determine the role of Aβ in tau maturation and neurotoxicity.
- To establish a novel primate model for early sporadic AD.
Main Methods:
- Injection of tau seeds from AD brains into the entorhinal cortex of macaques.
- Co-injection of oligomeric Aβ to assess its influence.
- Analysis of tau pathology spread, CSF biomarkers, and neurodegeneration over 18 months.
Main Results:
- Tau pathology spread from the entorhinal cortex to other brain regions, mimicking Braak stages I-IV.
- Aβ co-injection led to mature neurofibrillary tangles, increased total-tau, and neurodegeneration.
- Tau seeds alone increased CSF p-tau181 but did not cause mature pathology.
Conclusions:
- Misfolded tau exhibits prion-like properties in primates.
- Oligomeric Aβ is essential for tau pathology maturation and neuronal toxicity.
- This study provides a new primate model for early Alzheimer's disease.
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