Approaches to develop therapeutics to treat frontotemporal dementia

Elia, Lisa P.; Reisine, Terry; Alijagic, Amela; Finkbeiner, Steven

doi:10.1016/j.neuropharm.2020.107948

Cited by 11 publications

(11 citation statements)

References 141 publications

(148 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This notion may be useful in exploring SORT1-mediated PGRN upregulators, as SORT1 is a direct clearance receptor of PGRN. Other compounds, excluding anti-SORT1 mAbs, have been identified to be effective in increasing PGRN levels in cell lines derived from GRN mutation carriers (Capell et al, 2011;Cenik et al, 2011;Holler et al, 2016;Elia et al, 2020). Inhibitors of histone deacetylases (HDACs) was found to increase PGRN gene and protein expression through unknown mechanisms (Cenik et al, 2011).…”

Section: Discussion Expected Benefits Of Anti-sort1 Mab Compared Withmentioning

confidence: 99%

“…V-ATPase inhibitors enhanced PGRN expression or significantly elevated PGRN secretion via a translational mechanism independent of lysosomal degradation, autophagy, or endocytosis (Capell et al, 2011). Pharmacological inhibition of FOXO1, TRAP1/HSP90L, JMJD6, or ELK3 increased PGRN levels in neurons, inhibiting the activity of their gene products (Elia et al, 2020). Trehalose transcriptionally up-regulates PGRN expression in human and mouse models of GRN haploinsufficiency, and it rescues PGRN deficiency in human fibroblasts and neurons derived from induced pluripotent stem cells generated from GRN mutation carriers (Holler et al, 2016).…”

Section: Discussion Expected Benefits Of Anti-sort1 Mab Compared Withmentioning

confidence: 99%

“…A recent preclinical study has supported this notion by demonstrating that adeno-associated virus-driven expression of PGRN in the medial prefrontal cortex rescued social dominance deficits in a FTD model of Grn hetero-KO mice (Arrant et al, 2017). Drug discovery research has also investigated PGRN-boosting therapies in vitro by targeting epigenetic factors and transcription factors (Capell et al, 2011;Cenik et al, 2011;Holler et al, 2016;Elia et al, 2020). However, these approaches have not been tested in vivo.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation

et al. 2020

View full text Add to dashboard Cite

Progranulin (PGRN) haploinsufficiency associated with loss-of-function mutations in the granulin gene causes frontotemporal dementia (FTD). This suggests that increasing PGRN levels could have promising therapeutic implications for patients carrying GRN mutations. In this study, we explored the therapeutic potential of sortilin1 (SORT1), a clearance receptor of PGRN, by generating and characterizing monoclonal antibodies against SORT1. Anti-SORT1 monoclonal antibodies were generated by immunizing Sort1 knockout mice with SORT1 protein. The antibodies were classified into 7 epitope bins based on their competitive binding to the SORT1 protein and further defined by epitope bin-dependent characteristics, including SORT1-PGRN blocking, SORT1 down-regulation, and binding to human and mouse SORT1. We identified a positive correlation between PGRN up-regulation and SORT1 down-regulation. Furthermore, we also characterized K1-67 antibody via SORT1 down-regulation and binding to mouse SORT1 in vivo and confirmed that K1-67 significantly up-regulated PGRN levels in plasma and brain interstitial fluid of mice. These data indicate that SORT1 down-regulation is a key mechanism in increasing PGRN levels via anti-SORT1 antibodies and suggest that SORT1 is a potential target to correct PGRN reduction, such as that in patients with FTD caused by GRN mutation.

show abstract

Section: Discussion Expected Benefits Of Anti-sort1 Mab Compared Withmentioning

confidence: 99%

Section: Discussion Expected Benefits Of Anti-sort1 Mab Compared Withmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…These characteristics suggest that PGRN may be an important therapeutic target, and restoring PGRN levels may be an effective way to prevent and treat dementia. (Cui et al., 2019; Elia et al., 2020; Galimberti et al., 2018; Gass et al., 2012; Malik et al., 2019).…”

Section: Increasing Pgrn Level To Prevent Neurodegeneration In Dementiamentioning

confidence: 99%

Progranulin in neurodegenerative dementia

Wang

Zeng

Fang

et al. 2021

Journal of Neurochemistry

View full text Add to dashboard Cite

Dementia refers to an acquired clinical syndrome in which a person's cognitive level drops significantly, thereby interfering with his/her ability to perform activities related to occupation, family, social interaction, and daily life. The global prevalence of dementia is estimated to be 7% in the population aged over 65 years, with a slightly higher prevalence (8%-10%) in developed countries (due to their longer life spans in such countries) (Jia et al., 2020;Prince et al., 2013). With the acceleration of population aging, this condition is predicted to bring huge economic burdens to the world, especially in countries with a high prevalence of this condition.Dementia is mainly divided into two categories, namely, neurodegenerative and non-neurodegenerative dementia (Gale et al., 2018).The commonly occurring types of neurodegenerative dementia include Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). In addition to exposure to injury factors, the long-term or

show abstract

“…Neuropsychological assessments in patients with bv-FTD indicate impaired attention, working memory and EF, decreased social cognition, delayed recall, and some degrees of apraxia. [ 7 ]…”

Section: Introductionmentioning

confidence: 99%

Comparison of Design Fluency Test results among patients with Parkinson’s disease, frontotemporal dementia, and the control group

et al. 2021

View full text Add to dashboard Cite

Background: Design Fluency Test (DFT) is a nonverbal frame-free, nonstructured assessment of executive function (EF). Since previous studies evaluating EF in Parkinson's disease (PD) have mainly used verbal assessments for EF, this study aims to evaluate the pattern of executive domains in PD using DFT and to compare it with behavioral variant frontotemporal dementia (FTD) as a prototype for executive dysfunction and also with normal controls (NCs). Materials and Methods: Twenty-eight patients with PD, 27 with FTD, and 27 NCs were included in the study in Ayatollah Kashani Neuropsychiatry Clinic affiliated to Isfahan University of Medical Sciences from September 2019 to February 2020. All participants were assessed via semi-structured neuropsychiatric interview, questionnaire for demographic profile (age, handedness, gender, education, and marital status), duration of illness, comorbid medical condition, comorbid psychiatric illnesses and medications, DFT, Short Parkinson's Evaluation Scale, Frontal Assessment Battery, Judgment of Line Orientation, and Neuropsychiatry Unit Cognitive Assessment Tool. Results: Fixed condition novelty score was significantly different between FTD and PD ( P < 0.001), FTD and control ( P < 0.001), and also between PD and control ( P = 0.001). When free and fixed condition novelty scores were considered to predict diagnostic attribution, multinomial logistic regression revealed that odds ratio for free condition novelty score was 0.705 ( P = 0.005, 95% confidence interval [CI] = 0.553–0.899) and 0.494 ( P = 0.001, 95% CI = 0.328–0.744) in PD and FTD, respectively. The odds ratio for fixed condition novelty score was 0.772 ( P = 0.011, 95% CI = 0.632–0.942) and 0.449 ( P = 0.00, 95% CI = 0.292–0.691). Conclusion: DFT subscores can be helpful in diagnosis and differentiation between FTD and PD.

show abstract

Approaches to develop therapeutics to treat frontotemporal dementia

Cited by 11 publications

References 141 publications

Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation

Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation

Progranulin in neurodegenerative dementia

Comparison of Design Fluency Test results among patients with Parkinson’s disease, frontotemporal dementia, and the control group

Contact Info

Product

Resources

About