eNeuroJan 12, 2023

Increased Tau Protein Problems in Mice with P290S Mutation Combined with App NL-G-F Mutation

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Mar 25, 2026

Abstract

KI mice developed a significant increase in starting at 18 months of age.

Tau inclusions in KI mice increased with age, indicating a progressive accumulation of tau pathology.
The most significant tau pathology was observed in limbic areas, including the hippocampus, amygdala, and piriform/entorhinal cortex.
Dystrophic neurites containing assembled filamentous tau were present, as confirmed by electron microscopy.
Sarkosyl-insoluble brain extracts from 18-month-old KI and double-KI mice showed seed competency, with double-KI extracts being more effective in seeding.
Neurodegeneration was evident in the piriform cortex of KI mice starting from 18 months of age.
The KI mouse model may be useful for investigating the interactions between tau, Aβ, and neurodegeneration.

Simplified

Alzheimer's Disease (AD) is characterized by the pathologic assembly of amyloid β (Aβ) peptide, which deposits into extracellular plaques, and tau, which accumulates in intraneuronal inclusions. To investigate the link between Aβ and tau pathologies, experimental models featuring both pathologies are needed. We developed a mouse model featuring both tau and Aβ pathologies by knocking the P290S mutation into murineand crossing theseknock-in (KI) mice with theKI line.KI mice developed a small number of tau inclusions, which increased with age. The amount of was significantly larger inKI mice from 18 months of age onward. Tau pathology was higher in limbic areas, including hippocampus, amygdala, and piriform/entorhinal cortex. We also observed AT100-positive and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized byelectron microscopy. Using a cell-based tau seeding assay, we showed that Sarkosyl-insoluble brain extracts from both 18-month-oldKI andKI mice were seed competent, with brain extracts from double-KI mice seeding significantly more than those from theKI mice. Finally, we showed thatKI mice had neurodegeneration in the piriform cortex from 18 months of age. We suggest thatKI mice provide a good model for studying the interactions of aggregation-prone tau, Aβ, neuritic plaques, neurodegeneration, and aging. Mapt Mapt App Mapt App xMapt in situ Mapt App xMapt Mapt App xMapt App xMapt P290S NL-G-F P290S NL-G-F P290S P290S NL-G-F P290S P290S NL-G-F P290S NL-G-F P290S

Key numbers

6×

Increase in AT100-immunoreactive cells

At 18 months, AT100-immunoreactive cells were six times more prevalent in double-KI mice.

18 months

Age of neurodegeneration onset

Significant nerve cell loss was detected from 18 months onward in double-KI mice.

43×

Sarkosyl-insoluble tau increase

At 18 months, Sarkosyl-insoluble tau levels were 43 times higher in double-KI mice than in wild-type.

Full Text

We can’t show the full text here under this license.

View Full Text ↗

Funding

Competing interests

The authors declare no competing financial interests.

PubMed

Increased Tau Protein Problems in Mice with P290S Mutation Combined with App NL-G-F Mutation

Abstract

Key numbers

Full Text

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the longevity & aging brief

Abstract

Key numbers

Full Text

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the longevity & aging brief