In a groundbreaking study published in the journal Nature Neuroscience, researchers have discovered that a rare genetic mutation, known as APOE3-R136S, offers protection against Alzheimer’s disease (AD) pathologies. Specifically, the study aimed to investigate whether this mutation could protect against the detrimental effects of apolipoprotein E4 (APOE4), a genetic variant known to increase the risk of late-onset AD (LOAD).
LOAD is characterized by the accumulation of amyloid-beta and tau proteins, neuroinflammation, and neurodegeneration, all of which contribute to the development and progression of AD. It is estimated that APOE4 carriers contribute to 55% to 75% of AD cases, underscoring the significance of understanding the role of APOE4 in AD pathogenesis and identifying potential protective targets.
The APOE3-R136S variant has previously been found to offer protection against early-onset AD in carriers of the PSEN1-E280A mutation. Building on this knowledge, the researchers sought to investigate whether introducing the R136S mutation could mitigate the effects of APOE4-induced LOAD.
To conduct their experiment, the research team inserted the R136S mutation into the APOE4 allele of both human-induced pluripotent stem cells (hiPSCs) obtained from an AD patient and human APOE4 knock-in (E4-KI) mice. They then evaluated the effects of this mutation on APOE-induced tau pathology.
The researchers utilized isogenic hiPSC-derived neurons, including an APOE3 hiPSC line (E3), the parental APOE4 hiPSC line (E4), as well as homozygous (E4-S/S) and heterozygous (E4-R/S) mutated lines. By introducing the R136S mutation into the APOE4 loci, the researchers were able to assess its impact on the accumulation of phosphorylated tau (p-Tau) protein in the hippocampus.
Through immunochemistry techniques, the research team observed a significant reduction in p-Tau protein levels in the mice carrying the homozygous R136S mutation. Furthermore, the homozygous mutation was found to decrease the uptake of tau protein by human neurons, likely due to the defective binding of the mutation with heparin sulfate proteoglycans (HSPGs).
In addition to its effects on tau pathology, the R136S mutation also demonstrated protective effects against astrocytosis and microgliosis in the hippocampus, two processes associated with neurodegeneration. These effects were shown to be age-dependent, with the homozygous mutation offering more significant protection than the heterozygous mutation.
Furthermore, the researchers discovered that the R136S mutation led to a five-fold increase in APOE protein levels, suggesting that this mutation may help mitigate the harmful effects of APOE4 on gamma-aminobutyric acid (GABA)-ergic neurons.
Overall, this study highlights the potential of the rare APOE3-R136S mutation to protect against AD pathologies, particularly tau protein accumulation and neuroinflammation. These findings contribute valuable insights into the development of potential therapeutic strategies for the treatment and prevention of AD. Further research is needed to fully understand the mechanisms underlying the protective effects of this mutation and its clinical implications.
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1. Source: Coherent Market Insights, Public sources, Desk research
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