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.

Highlights

  • Alzheimer’s disease (AD) is the most common cause of age-related dementia, characterized by progressive cognitive decline, and widespread deposition of neuritic plaques and neurofibrillary tangles in the brain

  • To evaluate the levels of protein prenylation during the progression of AD, postmortem human brain tissue samples were obtained from the Religious Orders Study (ROS) participants with three different clinical diagnoses –no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer’s dementia [30]

  • The results showed that FT levels were significantly elevated in AD brains and a trend of increase in the MCI group (Fig. 2B), whereas Geranylgeranyl transferase (GGT) levels were similar among the three groups (Fig. 2C)

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Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of age-related dementia, characterized by progressive cognitive decline, and widespread deposition of neuritic plaques and neurofibrillary tangles in the brain. Farnesyltransferase (FT), geranylgeranyl transferase-1 (GGT-1; GGT), and -2 (GGT-2, known as RabGGT) covalently attach FPP or GGPP to a cysteine residue in the C-terminal CAAX motif of target proteins [9] (Fig. 1). These posttranslational modification processes, namely farnesylation and geranylgeranylation, are collectively called protein prenylation [10]. The superfamily of small GTPases, including Ras, Rho, and Rab GTPases, is the most widely studied group of proteins that are modified by prenylation These small GTPases and their downstream signaling pathways regulate a wide range of cellular processes such as regulation of cell cycle entry, endosomal trafficking, cell adhesion and migration

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