ArticleActa neuropathologica communications2021
Protein farnesylation is upregulated in Alzheimer's human brains and neuron-specific suppression of farnesyltransferase mitigates pathogenic processes in Alzheimer's model mice.
Article in Acta neuropathologica communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- Mechanisms and Predisposing Conditions for Statin-Induced New-Onset Type 2 Diabetes Mellitus: A Paradox Relative to Their Pleiotropic Metabolic Effects.Endocrinology, diabetes & metabolism · 2026Review
- Chronic Lithium Exposure Reshapes PI3K-mTOR-linked Proteostatic Networks in the Hippocampus of an Alzheimer's Disease Mouse Model.Molecular neurobiology · 2026Article
- HDL-mimetic peptide treatment reverses APOE4-induced transcriptomic and lipidomic alterations in the brain of humanized APOE mice.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Organotellurium Probes Enable One-step Single-cell Analysis of Post-translational Modification.Journal of the American Chemical Society · 2026Article
- Statins and genetic inhibition of the mevalonate pathway activate an ATF3-STMN2 regenerative program.bioRxiv : the preprint server for biology · 2026Article
- Article
- Whole Transcriptome RNA-Seq Reveals Drivers of Pathological Dysfunction in a Transgenic Model of Alzheimer's Disease.Molecular neurobiology · 2025Article
- The HDL-Mimetic Peptide 4F Mitigates Vascular and Cortical Amyloid Pathology and Associated Neuroinflammation in a Transgenic Mouse Model of Cerebral Amyloid Angiopathy and Alzheimer's Disease.Molecular neurobiology · 2025Article
- Regulation of glial ApoE secretion by the mevalonate pathway is independent of ApoE isoform.Journal of Alzheimer's disease : JAD · 2025Article
- Loss of TREM2 diminishes CAA despite an overall increase of amyloid load in Tg-SwDI mice.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Protein lipidation in health and disease: molecular basis, physiological function and pathological implication.Signal transduction and targeted therapy · 2024Review
- Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model.Frontiers in microbiology · 2024Article
- Impaired Autophagic-Lysosomal Fusion in Parkinson's Patient Midbrain Neurons Occurs through Loss of ykt6 and Is Rescued by Farnesyltransferase Inhibition.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Deletion of Small GTPase H-Ras Rescues Memory Deficits and Reduces Amyloid Plaque-Associated Dendritic Spine Loss in Transgenic Alzheimer's Mice.Molecular neurobiology · 2023Article
- Article
- Mechanistic insight into impact of phosphorylation on the enzymatic steps of farnesyltransferase.Protein science : a publication of the Protein Society · 2022Article
- Farnesyltransferase inhibitor LNK-754 attenuates axonal dystrophy and reduces amyloid pathology in mice.Molecular neurodegeneration · 2022Article
- A Farnesyltransferase Inhibitor Restores Cognitive Deficits inThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- A method for simultaneous detection of small and long RNA biotypes by ribodepleted RNA-Seq.Scientific reports · 2022Article
- Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer's disease.Frontiers in molecular neuroscience · 2022Review
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Authors and funding
6 authors at 3 institutions in 3 countries.
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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.
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