Genetic colocalization of cathepsins H,D,and L1 with Alzheimer's disease: Implications for biomarker and therapeutic target discovery

Abstract

Background

Cathepsins, a family of lysosomal proteases, have been implicated in Alzheimer's disease (AD) pathogenesis through their involvement in amyloid-β protein precursor processing and neuroinflammation. However, the specific roles of different cathepsins in AD remain unclear.

Objective

This study aimed to investigate the genetic associations and potential causal relationships between cathepsins and AD, using Mendelian randomization (MR) to explore their roles as biomarkers and therapeutic targets.

Methods

A two-sample MR analysis was conducted using genome-wide association study data for AD and cathepsins. Genetic variants associated with cathepsin expression were used as instrumental variables. Forward MR assessed the causal effect of cathepsins on AD, while reverse MR explored the impact of AD on cathepsin levels. Colocalization analysis was performed to identify shared genetic variants between cathepsins and AD.

Results

Cathepsin H was significantly associated with an increased risk of AD (p = 0.0034, OR = 1.04), with consistent results across multiple MR methods. Colocalization analysis revealed a significant genetic overlap between Cathepsin L1 and AD (PP.H4 = 100%), suggesting a shared genetic basis.

Conclusions

Cathepsin H may be a potential risk factor for AD, while Cathepsin L1 shows promise as a therapeutic target and biomarker due to its genetic overlap with AD. Further research is needed to explore the mechanisms by which these cathepsins influence AD progression and to assess their therapeutic potential in diverse populations.

Keywords

Alzheimer's disease cathepsin genetic associations Mendelian randomization neurodegeneration protease activity

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References

Livingston

Sommerlad

Orgeta

, et al. Dementia prevention, intervention, and care. Lancet 2017; 390: 2673–2734.

Prince

Wimo

Guerchet

, et al. World Alzheimer Report 2015. The global impact of dementia: An analysis of prevalence, incidence, cost, and trends. London, UK: Alzheimer's Disease International, 2015.

Patterson

. World Alzheimer Report 2018. The state of the art of dementia research: New frontiers. London, UK: Alzheimer's Disease International, 2018.

Jack

Jr Knopman

Jagust

, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 2010; 9: 119–128.

Spires-Jones

Hyman

. The intersection of amyloid beta and tau at synapses in Alzheimer's disease. Neuron 2014; 82: 756–771.

Hardy

Selkoe

. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002; 297: 353–356.

2023 Alzheimer's disease facts and figures. Alzheimers Dement 2023; 19: 1598–1695.

Schulz

Martire

. Family caregiving of persons with dementia: prevalence, health effects, and support strategies. Am J Geriat Psychiatr 2004; 12: 240–249.

Brookmeyer

Abdalla

Kawas

, et al. Forecasting the prevalence of preclinical and clinical Alzheimer's disease in the United States. Alzheimers Dement 2018; 14: 121–129.

10.

Jia

Wei

Chen

, et al. The cost of Alzheimer's disease in China and re-estimation of costs worldwide. Alzheimers Dement 2018; 14: 483–491.

11.

Stoka

Turk

. Lysosomal cathepsins and their regulation in aging and neurodegeneration. Ageing Res Rev 2016; 32: 22–37.

12.

Vidak

Javorsek

Vizovisek

, et al. Cysteine cathepsins and their extracellular roles: shaping the microenvironment. Cells 2019; 8: 264.

13.

Hook

Kindy

. The cysteine protease inhibitor, e64d, reduces brain amyloid-beta and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin b, but not bace1, beta-secretase activity. J Alzheimers Dis 2011; 26: 387–408.

14.

Mueller-Steiner

Zhou

Arai

, et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron 2006; 51: 703–714.

15.

Hook

Toneff

Bogyo

, et al. Inhibition of cathepsin B reduces beta-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate beta-secretase of Alzheimer's disease. Biol Chem 2005; 386: 931–940.

16.

Chai

Chong

Weng

, et al. Lysosomal cathepsin D is upregulated in Alzheimer's disease neocortex and may be a marker for neurofibrillary degeneration. Brain Pathol 2019; 29: 63–74.

17.

Bernstein

Keilhoff

. Putative roles of cathepsin B in Alzheimer's disease pathology: the good, the bad, and the ugly in one? Neural Regen Res 2018; 13: 2100–2101.

18.

Yang

Kuan

Zhang

, et al. Macrophage-mediated controlled release of cysteine protease inhibitor from PLGA-PEG/hydroxyapatite microspheres for targeting cathepsin S in Alzheimer's disease. Eur Polym J 2024; 214: 113151.

19.

Jangra

Bajad

Singh

, et al. Identification of novel potential cathepsin-B inhibitors through pharmacophore-based virtual screening, molecular docking, and dynamics simulation studies for the treatment of Alzheimer's disease. Mol Divers 2024; 28: 4381–4401.

20.

Rastegar

Nouri

Masoudi

, et al. Role of cathepsins in Alzheimer's disease: a systematic review. J Med Biol Sci 2018; 7: 1–10.

21.

Benes

Vetvicka

Fusek

. Cathepsin D–many functions of one aspartic protease. Crit Rev Oncol Hematol 2008; 68: 12–28.

22.

Reiser

Adair

Reinheckel

. Specialized roles for cysteine cathepsins in health and disease. J Clin Invest 2010; 120: 3421–3431.

23.

Davies

Holmes

Davey

. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 2018; 362: k601.

24.

Smith

Ebrahim

. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 2004; 33: 30–42.

25.

Lawlor

Harbord

Sterne

, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008; 27: 1133–1163.

26.

von Elm

Altman

Egger

, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Int J Surg 2014; 12: 1495–1499.

27.

Boef

Dekkers

le Cessie

. Mendelian randomization studies: a review of the approaches used and the quality of reporting. Int J Epidemiol 2015; 44: 496–511.

28.

Burgess

Thompson

. Interpreting findings from Mendelian randomization using the MR-egger method. Eur J Epidemiol 2017; 32: 377–389.

29.

Bowden

Holmes

. Meta-analysis and Mendelian randomization: a review. Res Synth Methods 2019; 10: 486–496.

30.

Brion

Shakhbazov

Visscher

. Calculating statistical power in Mendelian randomization studies. Int J Epidemiol 2013; 42: 1497–1501.

31.

Bowden

Davey

Haycock

, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 2016; 40: 304–314.

32.

Hartwig

Davey

Bowden

. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol 2017; 46: 1985–1998.

33.

Bowden

Del

GMF

Minelli

, et al. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-egger regression: the role of the I2 statistic. Int J Epidemiol 2016; 45: 1961–1974.

34.

Pecar

Kos

Mitrovic

. Compensational role between cathepsins. Biochimie 2024; 226: 62–76.

35.

Suire

Abdul-Hay

Sahara

, et al. Cathepsin D regulates cerebral Abeta42/40 ratios via differential degradation of Abeta42 and Abeta40. Alzheimers Res Ther 2020; 12: 80.

36.

Lambeth

Julian

. Proteolysis of amyloid beta by lysosomal enzymes as a function of fibril morphology. ACS Omega 2021; 6: 31520–31527.

37.

Davis

Cook

Hall

, et al. Patients with sporadic FTLD exhibit similar increases in lysosomal proteins and storage material as patients with FTD due to GRN mutations. Acta Neuropathol Commun 2023; 11: 70.

38.

Yao

Zhao

Khan

, et al. Role of autophagy in prion protein-induced neurodegenerative diseases. Acta Bioch Bioph Sin (Shanghai) 2013; 45: 494–502.

39.

Wang

, et al. The regulation of N-terminal Huntingtin (Htt552) accumulation by Beclin1. Acta Pharmacol Sin 2012; 33: 743–751.

40.

Islam

Nagakannan

Shcholok

, et al. Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer's disease. Aging Cell 2022; 21: e13531.

41.

Rustamzadeh

Tafakhori

Ariaei

, et al. Targeting Caspases 3/6 and Cathepsins L/B may decrease laminopathy-induced apoptosis in Alzheimer's disease. J Alzheimers Dis 2024; 101: 211–221.

42.

Yoshiyama

Arai

Oki

, et al. Expression of invariant chain and pro-cathepsin L in Alzheimer's brain. Neurosci Lett 2000; 290: 125–128.

43.

Batkulwar

Godbole

Banarjee

, et al. Advanced glycation end products modulate amyloidogenic APP processing and tau phosphorylation: a mechanistic link between glycation and the development of Alzheimer's disease. ACS Chem Neurosci 2018; 9: 988–1000.

44.

Viswanathan

Hoover

Hwang

, et al. Nonpeptidic lysosomal modulators derived from z-phe-ala-diazomethylketone for treating protein accumulation diseases. ACS Med Chem Lett 2012; 3: 920–924.

45.

Xue

Shen

Pan

. Constrained maximum likelihood-based Mendelian randomization robust to both correlated and uncorrelated pleiotropic effects. Am J Hum Genet 2021; 108: 1251–1269.

46.

Wong

Liang

Jiang

, et al. Mutation of the gene for the human lysosomal serine protease cathepsin G is not the cause of aberrant APP processing in familial Alzheimer disease. Neurosci Lett 1993; 152: 96–98.

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