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Amyloid Beta Is Internalized via Macropinocytosis, an HSPG- and Lipid Raft-Dependent and Rac1-Mediated Process

Keyoumu Nazere1, Tetsuya Takahashi1,2, Naoyuki Hara1

  • 1Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

Frontiers in Molecular Neuroscience
|October 3, 2022
PubMed

Insights

Oligomerized amyloid beta (Aβ) enters cells via macropinocytosis, a process involving lipid rafts and heparan sulfate proteoglycans. This cellular uptake mechanism is crucial for understanding Alzheimer's disease pathophysiology.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Intracellular amyloid beta peptide (Aβ) accumulation is implicated in Alzheimer's disease pathogenesis.
  • Understanding the cellular uptake mechanisms of extracellular Aβ is critical for disease research.

Purpose of the Study:

  • To investigate the cellular internalization mechanisms of oligomerized amyloid beta (oAβ).
  • To determine the specific endocytic pathways involved in oAβ uptake by neuronal cells.

Main Methods:

  • Utilized Neuro2A and SH-SY5Y cell lines to study Aβ internalization.
  • Investigated the role of lipid rafts and heparan sulfate proteoglycans using cholesterol depletion and trypsin treatment.
  • Examined the effect of macropinocytosis inhibitors (ethylisopropyl amiloride, wortmannin) on oAβ uptake.
  • Assessed Rac1 activity in oAβ-treated cells.

Main Results:

  • Neuro2A and SH-SY5Y cells internalized oAβ in a time- and dose-dependent manner.
  • oAβ uptake was reduced by cholesterol depletion and trypsin treatment, suggesting lipid raft and heparan sulfate proteoglycan involvement.
  • Macropinocytosis inhibitors significantly decreased oAβ internalization.
  • oAβ treatment increased Rac1 activity, indicating macropinocytosis regulation by small GTPases.

Conclusions:

  • Macropinocytosis is a primary endocytic pathway for the cellular uptake of oligomerized amyloid beta 42 (oAβ42).
  • The internalization process involves lipid raft-dependent and heparan sulfate proteoglycan-mediated mechanisms.
  • Rac1-regulated macropinocytosis is key to oAβ entry into cells.
Keywords:
Alzheimer’s diseaseHSPGRac1amyloid – betalipid raftmacropinocytosis

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