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

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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.

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Data Availability

N/A.

Abbreviations

AA :

Amino acids

AD :

Alzheimer’s disease

AMPA :

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

Apaf-1 :

Apoptosis protease-activating factor-1 adapter molecule

Asp421 :

Asparginine 421

AT8 :

Marker of tau hyperphosphorylation in Ser202/Thr305 sites

ATP :

Adenosine triphosphate

CA :

Cornus ammonis

CAMKII :

Ca2+/calmodulin-dependent protein kinase II

Cdk2 :

Cyclin-dependent kinase 2

Cdk5 :

Cyclin-dependent kinase 5

CNS :

Central nervous system

CsA :

Cyclosporine A

DNA :

Deoxyribonucleic acid

DRP1 :

Dynamin-related protein 1

fEPSPs :

Field excitatory post-synaptic potentials

GSK-3β :

Glycogen synthase kinase-3 beta

HEK :

Human embryonic kidney cells

IMM :

Inner mitochondrial membrane

LDH :

Lactate dehydrogenase

LTP :

Long-term potentiation

LTD :

Long terminal depression

MAP :

Microtubule-associated protein

MAPK :

Mitogen-activated protein kinase

MCI :

Mild cognitive impairment

MCU :

Mitochondrial calcium uniporter

mEPSCs :

Miniature excitatory post-synaptic currents

MFN :

Mitofusins

mPTP :

Mitochondrial permeability transition pore

N2a :

Neuroblastoma 2a

NCI :

Non-cognitively impaired

NFTs :

Neurofibrillary tangles

NMDA :

N-Methyl-D-aspartate

NPS :

Neurites plaques

NPTs :

Neuropil threads

NR1 :

N-Methyl-D-aspartic receptor 1

NR2B :

N-Methyl-D-aspartic receptor 2

Nrf2 :

Nuclear factor (erythroid-derived 2)-like 2

OMM :

Outer mitochondrial membrane

Opa1 :

Optic atrophy protein 1

OXPHOS :

Oxidative phosphorylation

PIPES :

Piperazine-N,N′-bis(2-ethane sulfonic acid)

PKA :

Protein kinase A

PKC :

Protein kinase C

PSD95 :

Post-synaptic density protein 95

ROS :

Reactive oxygen species

SNAP-25 :

Synaptosome-associated protein

TRAK :

Trafficking kinesin-binding

zVAD-fmk :

Carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone

8oxodG :

8-Oxo-2′-deoxyguanosine

ΔΨm :

Mitochondrial membrane potential

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Funding

This work was supported by ANID, GRANT FONDECYT # 1200178, Santiago, Chile. MAO thanked Universidad Autónoma de Chile (PhD fellowship).

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  1. Laboratory of Neurodegenerative Diseases, Facultad de Ciencias de La Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, El Llano Subercaseaux 2801, 5to Piso, San Miguel, 8910060, Santiago, Chile

    Margrethe A. Olesen & Rodrigo A. Quintanilla

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  1. Margrethe A. Olesen
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MAO made the figures and conceived, wrote, and edited manuscript; RAQ conceived, edited, and financed this research.

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Correspondence to Rodrigo A. Quintanilla.

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Olesen, M.A., Quintanilla, R.A. Pathological Impact of Tau Proteolytical Process on Neuronal and Mitochondrial Function: a Crucial Role in Alzheimer’s Disease. Mol Neurobiol 60, 5691–5707 (2023). https://doi.org/10.1007/s12035-023-03434-4

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