Abstract
The pathogenic mechanisms underlying the development of Alzheimer’s disease (AD) remain elusive and to date there are no effective prevention or treatment for AD. Farnesyltransferase (FT) catalyzes a key posttranslational modification process called farnesylation, in which the isoprenoid farnesyl pyrophosphate is attached to target proteins, facilitating their membrane localization and their interactions with downstream effectors. Farnesylated proteins, including the Ras superfamily of small GTPases, are involved in regulating diverse physiological and pathological processes. Emerging evidence suggests that isoprenoids and farnesylated proteins may play an important role in the pathogenesis of AD. However, the dynamics of FT and protein farnesylation in human brains and the specific role of neuronal FT in the pathogenic progression of AD are not known. Here, using postmortem brain tissue from individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), or Alzheimer’s dementia, we found that the levels of FT and membrane-associated H-Ras, an exclusively farnesylated protein, and its downstream effector ERK were markedly increased in AD and MCI compared with NCI. To elucidate the specific role of neuronal FT in AD pathogenesis, we generated the transgenic AD model APP/PS1 mice with forebrain neuron-specific FT knockout, followed by a battery of behavioral assessments, biochemical assays, and unbiased transcriptomic analysis. Our results showed that the neuronal FT deletion mitigates memory impairment and amyloid neuropathology in APP/PS1 mice through suppressing amyloid generation and reversing the pathogenic hyperactivation of mTORC1 signaling. These findings suggest that aberrant upregulation of protein farnesylation is an early driving force in the pathogenic cascade of AD and that targeting FT or its downstream signaling pathways presents a viable therapeutic strategy against AD.
| Original language | English (US) |
|---|---|
| Article number | 129 |
| Journal | Acta Neuropathologica Communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2021 |
Bibliographical note
Funding Information:This work was supported in part by grants from the National Institute on Aging of the National Institutes of Health (R01AG031846, RF1AG056976, RF1AG058081, P30AG10161, and R01AG15819) and the College of Pharmacy at the University of Minnesota.
Funding Information:
We thank Debra Magnuson, Karen Skish, and Gregory Klein at Rush University Alzheimer’s Research Center for selecting and providing the postmortem human brain specimens, and Gunter Eckert at the University of Giessen for providing the APP695-overexpressing and control SH-SY5Y cells. We also thank Andrea Gram for breeding, maintaining and genotyping the experimental mice, Kyle LeBlanc for preparing mouse brain sections and immunostaining, and Juan E. Abrahante Lloréns at the University of Minnesota Informatics Institute for assisting with RNA-seq data analysis. AJ was partly supported by the Kwanjeong Educational Foundation Overseas Scholarship from South Korea.
Funding Information:
We thank Debra Magnuson, Karen Skish, and Gregory Klein at Rush University Alzheimer’s Research Center for selecting and providing the postmortem human brain specimens, and Gunter Eckert at the University of Giessen for providing the APP695-overexpressing and control SH-SY5Y cells. We also thank Andrea Gram for breeding, maintaining and genotyping the experimental mice, Kyle LeBlanc for preparing mouse brain sections and immunostaining, and Juan E. Abrahante Lloréns at the University of Minnesota Informatics Institute for assisting with RNA-seq data analysis. AJ was partly supported by the Kwanjeong Educational Foundation Overseas Scholarship from South Korea.
Publisher Copyright:
© 2021, The Author(s).
Keywords
- Alzheimer’s disease
- Cholesterol
- Farnesyltransferase
- Isoprenoids
- Protein prenylation
- Small GTPases