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Profiling tyrosine kinase inhibitors as AD therapeutics in a mouse model of AD

Hyun-Ju Lee1, Jeong-Woo Hwang2, Jin-Hee Park2,3

  • 1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Daegu, 41068, Republic of Korea. hjlee@kbri.re.kr.

Molecular Brain
|August 14, 2023
PubMed

Insights

Not all tyrosine kinase inhibitors (TKIs) effectively treat Alzheimer's disease (AD) pathology in mouse models. Ibrutinib showed therapeutic benefits, while PD180970 worsened tau pathology, and cabozantinib had mixed results, highlighting the need for careful drug selection.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • Alzheimer's disease (AD) involves amyloid-β (Aβ) plaques, tauopathy, neuroinflammation, and cognitive decline.
  • Protein kinases are increasingly linked to AD pathology, making tyrosine kinase inhibitors (TKIs) potential therapeutic candidates.

Purpose of the Study:

  • To investigate the selective effects of three TKIs—ibrutinib, PD180970, and cabozantinib—on early-stage AD pathology in 5xFAD mice.
  • To determine if different TKIs exhibit varying therapeutic potential for Alzheimer's disease.

Main Methods:

  • Administration of ibrutinib, PD180970, or cabozantinib (10 mg/kg, i.p.) to 5xFAD mice.
  • Assessment of Aβ plaque load, tau hyperphosphorylation, neuroinflammation, and astrogliosis.
  • Comparison of the therapeutic efficacy of the tested TKIs on AD hallmarks.

Main Results:

  • Ibrutinib significantly reduced Aβ plaque number, tau hyperphosphorylation, and neuroinflammation.
  • PD180970 failed to alter Aβ plaques or neuroinflammation but exacerbated tau hyperphosphorylation.
  • Cabozantinib showed no effect on amyloidopathy but partially reduced tau hyperphosphorylation and astrogliosis.

Conclusions:

  • The therapeutic efficacy of TKIs in Alzheimer's disease mouse models is not universal.
  • Drug optimization, including dosage, timing, and administration route, is crucial for repurposing TKIs as AD therapeutics.
Keywords:
Alzheimer’s diseaseAmyloid-βCabozantinibIbrutinibNeuroinflammationPD180970TauTyrosine kinase inhibitors

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