Pathological Impact of Tau Proteolytical Process on Neuronal and Mitochondrial Function: a Crucial Role in Alzheimer's Disease

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2023 Jun 18

PMID 37332018

Authors

Margrethe A Olesen

Rodrigo A Quintanilla

Affiliations

Soon will be listed here.

Abstract

Tau protein plays a pivotal role in the central nervous system (CNS), participating in microtubule stability, axonal transport, and synaptic communication. Research interest has focused on studying the role of post-translational tau modifications in mitochondrial failure, oxidative damage, and synaptic impairment in Alzheimer's disease (AD). Soluble tau forms produced by its pathological cleaved induced by caspases could lead to neuronal injury contributing to oxidative damage and cognitive decline in AD. For example, the presence of tau cleaved by caspase-3 has been suggested as a relevant factor in AD and is considered a previous event before neurofibrillary tangles (NFTs) formation.Interestingly, we and others have shown that caspase-cleaved tau in N- or C- terminal sites induce mitochondrial bioenergetics defects, axonal transport impairment, neuronal injury, and cognitive decline in neuronal cells and murine models. All these abnormalities are considered relevant in the early neurodegenerative manifestations such as memory and cognitive failure reported in AD. Therefore, in this review, we will discuss for the first time the importance of truncated tau by caspases activation in the pathogenesis of AD and how its negative actions could impact neuronal function.

Citing Articles

Newer Therapeutic Approaches in Treating Alzheimer's Disease: A Comprehensive Review.

Reddi Sree R, Kalyan M, Anand N, Mani S, Gorantla V, Sakharkar M ACS Omega. 2025; 10(6):5148-5171.

PMID: 39989768 PMC: 11840625. DOI: 10.1021/acsomega.4c05527.

The Interplay Between Accumulation of Amyloid-Beta and Tau Proteins, PANoptosis, and Inflammation in Alzheimer's Disease.

Zhuang X, Lin J, Song Y, Ban R, Zhao X, Xia Z Neuromolecular Med. 2025; 27(1):2.

PMID: 39751702 DOI: 10.1007/s12017-024-08815-z.

Neuromodulation by nanozymes and ultrasound during Alzheimer's disease management.

Karthika V, Sridharan B, Nam J, Kim D, Lim H J Nanobiotechnology. 2024; 22(1):139.

PMID: 38555420 PMC: 10981335. DOI: 10.1186/s12951-024-02406-7.

Exploring the significance of caspase-cleaved tau in tauopathies and as a complementary pathology to phospho-tau in Alzheimer's disease: implications for biomarker development and therapeutic targeting.

Rizzi L, Grinberg L Acta Neuropathol Commun. 2024; 12(1):36.

PMID: 38419122 PMC: 10900669. DOI: 10.1186/s40478-024-01744-9.

Caspase-3 cleaved tau impairs mitochondrial function through the opening of the mitochondrial permeability transition pore.

Perez M, Ibarra-Garcia-Padilla R, Tang M, Porter Jr G, Johnson G, Quintanilla R Biochim Biophys Acta Mol Basis Dis. 2023; 1870(1):166898.

PMID: 37774936 PMC: 11361306. DOI: 10.1016/j.bbadis.2023.166898.

References

Mietelska-Porowska A, Wasik U, Goras M, Filipek A, Niewiadomska G . Tau protein modifications and interactions: their role in function and dysfunction. Int J Mol Sci. 2014; 15(3):4671-713. PMC: 3975420. DOI: 10.3390/ijms15034671. View

Yen S, Liu W, Hall F, Yan S, Stern D, Dickson D . Alzheimer neurofibrillary lesions: molecular nature and potential roles of different components. Neurobiol Aging. 1995; 16(3):381-7. DOI: 10.1016/0197-4580(95)00022-7. View

Wang J, Wang Z, Tian Q . Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer's disease. Neurosci Bull. 2014; 30(2):359-66. PMC: 5562660. DOI: 10.1007/s12264-013-1415-y. View

Braak H, Braak E, Grundke-Iqbal I, Iqbal K . Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci Lett. 1986; 65(3):351-5. DOI: 10.1016/0304-3940(86)90288-0. View

de Calignon A, Fox L, Pitstick R, Carlson G, Bacskai B, Spires-Jones T . Caspase activation precedes and leads to tangles. Nature. 2010; 464(7292):1201-4. PMC: 3091360. DOI: 10.1038/nature08890. View

Kanno T, Tsuchiya A, Nishizaki T . Hyperphosphorylation of Tau at Ser396 occurs in the much earlier stage than appearance of learning and memory disorders in 5XFAD mice. Behav Brain Res. 2014; 274:302-6. DOI: 10.1016/j.bbr.2014.08.034. View

Rohn T, Rissman R, Davis M, Kim Y, Cotman C, Head E . Caspase-9 activation and caspase cleavage of tau in the Alzheimer's disease brain. Neurobiol Dis. 2002; 11(2):341-54. DOI: 10.1006/nbdi.2002.0549. View

Horowitz P, Patterson K, Guillozet-Bongaarts A, Reynolds M, Carroll C, Weintraub S . Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer's disease. J Neurosci. 2004; 24(36):7895-902. PMC: 6729917. DOI: 10.1523/JNEUROSCI.1988-04.2004. View

Sokolow S, Henkins K, Bilousova T, Gonzalez B, Vinters H, Miller C . Pre-synaptic C-terminal truncated tau is released from cortical synapses in Alzheimer's disease. J Neurochem. 2014; 133(3):368-79. PMC: 4397171. DOI: 10.1111/jnc.12991. View

10.

Kang H, Yoon W, Moon G, Kim D, Sohn S, Kwon H . Caspase-3-mediated cleavage of PHF-1 tau during apoptosis irrespective of excitotoxicity and oxidative stress: an implication to Alzheimer's disease. Neurobiol Dis. 2005; 18(3):450-8. DOI: 10.1016/j.nbd.2004.12.004. View

11.

Matthews-Roberson T, Quintanilla R, Ding H, Johnson G . Immortalized cortical neurons expressing caspase-cleaved tau are sensitized to endoplasmic reticulum stress induced cell death. Brain Res. 2008; 1234:206-12. PMC: 2572685. DOI: 10.1016/j.brainres.2008.07.111. View

12.

Quintanilla R, Matthews-Roberson T, Dolan P, Johnson G . Caspase-cleaved tau expression induces mitochondrial dysfunction in immortalized cortical neurons: implications for the pathogenesis of Alzheimer disease. J Biol Chem. 2009; 284(28):18754-66. PMC: 2707209. DOI: 10.1074/jbc.M808908200. View

13.

Quntanilla R, Tapia-Monsalves C . The Role of Mitochondrial Impairment in Alzheimer´s Disease Neurodegeneration: The Tau Connection. Curr Neuropharmacol. 2020; 18(11):1076-1091. PMC: 7709157. DOI: 10.2174/1570159X18666200525020259. View

14.

Morio B, Panthu B, Bassot A, Rieusset J . Role of mitochondria in liver metabolic health and diseases. Cell Calcium. 2021; 94:102336. DOI: 10.1016/j.ceca.2020.102336. View

15.

de Assis Fernandes Caldeira D, Weiss D, Rocco P, Silva P, Cruz F . Mitochondria in Focus: From Function to Therapeutic Strategies in Chronic Lung Diseases. Front Immunol. 2021; 12:782074. PMC: 8649841. DOI: 10.3389/fimmu.2021.782074. View

16.

Perez M, Vergara-Pulgar K, Jara C, Cabezas-Opazo F, Quintanilla R . Caspase-Cleaved Tau Impairs Mitochondrial Dynamics in Alzheimer's Disease. Mol Neurobiol. 2017; 55(2):1004-1018. DOI: 10.1007/s12035-017-0385-x. View

17.

Quintanilla R, Tapia-Monsalves C, Vergara E, Perez M, Aranguiz A . Truncated Tau Induces Mitochondrial Transport Failure Through the Impairment of TRAK2 Protein and Bioenergetics Decline in Neuronal Cells. Front Cell Neurosci. 2020; 14:175. PMC: 7406829. DOI: 10.3389/fncel.2020.00175. View

18.

Briel N, Pratsch K, Roeber S, Arzberger T, Herms J . Contribution of the astrocytic tau pathology to synapse loss in progressive supranuclear palsy and corticobasal degeneration. Brain Pathol. 2020; 31(4):e12914. PMC: 8412068. DOI: 10.1111/bpa.12914. View

19.

Binder L, Frankfurter A, REBHUN L . The distribution of tau in the mammalian central nervous system. J Cell Biol. 1985; 101(4):1371-8. PMC: 2113928. DOI: 10.1083/jcb.101.4.1371. View

20.

Hanger D, Goniotaki D, Noble W . Synaptic Localisation of Tau. Adv Exp Med Biol. 2020; 1184:105-112. DOI: 10.1007/978-981-32-9358-8_9. View