Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Nov 17;25(22):12335.
doi: 10.3390/ijms252212335.

The Mechanistic Link Between Tau-Driven Proteotoxic Stress and Cellular Senescence in Alzheimer's Disease

Karthikeyan Tangavelou  1 , Kiran Bhaskar  1   2
Affiliations
Review

The Mechanistic Link Between Tau-Driven Proteotoxic Stress and Cellular Senescence in Alzheimer's Disease

Karthikeyan Tangavelou et al. Int J Mol Sci. .

Abstract

In Alzheimer's disease (AD), tau dissociates from microtubules (MTs) due to hyperphosphorylation and misfolding. It is degraded by various mechanisms, including the 20S proteasome, chaperone-mediated autophagy (CMA), 26S proteasome, macroautophagy, and aggrephagy. Neurofibrillary tangles (NFTs) form upon the impairment of aggrephagy, and eventually, the ubiquitin chaperone valosin-containing protein (VCP) and heat shock 70 kDa protein (HSP70) are recruited to the sites of NFTs for the extraction of tau for the ubiquitin-proteasome system (UPS)-mediated degradation. However, the impairment of tau degradation in neurons allows tau to be secreted into the extracellular space. Secreted tau can be monomers, oligomers, and paired helical filaments (PHFs), which are seeding competent pathological tau that can be endocytosed/phagocytosed by healthy neurons, microglia, astrocytes, oligodendrocyte progenitor cells (OPCs), and oligodendrocytes, often causing proteotoxic stress and eventually triggers senescence. Senescent cells secrete various senescence-associated secretory phenotype (SASP) factors, which trigger cellular atrophy, causing decreased brain volume in human AD. However, the molecular mechanisms of proteotoxic stress and cellular senescence are not entirely understood and are an emerging area of research. Therefore, this comprehensive review summarizes pertinent studies that provided evidence for the sequential tau degradation, failure, and the mechanistic link between tau-driven proteotoxic stress and cellular senescence in AD.

Keywords: Alzheimer’s disease; aggrephagy; autophagy; cellular senescence; nucleophagy; proteotoxic stress; senolytic drugs; tau; tauopathy; ubiquitin–proteasome system.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
20S proteasomal degradation of tau. The structure of the 20S proteasome consists of 7 different α subunit proteins (α1–α7—blue) and β subunit proteins (β1–β7—light red) in which β1, β2, and β5 subunits are constitutively catalytic active. The heptameric α subunits form an outer ring-like structure at the top and bottom of the inner two layers of heptameric β subunit proteins, stacked antiparallelly as an inner ring-like structure. The 20S proteasome can degrade natively unfolded tau. But, it does not degrade folded, phosphorylated (conformational changed), and ubiquitinated tau because of the absence of protein unfoldase and deubiquitinase activities, which are required to unfold and deubiquitinate tau before entering into the catalytic β subunit core proteins. Abbreviation: Ub, ubiquitin.
Figure 2
Figure 2
Overview of dynamics of tau degradation in AD. The degradation pathway for tau is selected based on the diversity of tau species based on their structure and post-translational modifications. In AD, non-ubiquitinated tau substrates, including unfolded and misfolded tau, can be degraded by the 20S proteasome and CMA, respectively. Misfolded ubiquitinated tau substrates, including phosphorylated and acetylated tau, can be degraded by the 26S proteasome and macroautophagy (autophagy), respectively. Hyperubiquitinated aqueous tau aggregates are degraded by liquid-phase aggrephagy, whereas solid tau aggregates of NFTs with or without ubiquitin chains are degraded by solid-phase aggrephagy. The ubiquitin chaperone, VCP/p97 ATPase, binds to HSP70 and synergistically extracts tau from NFTs for the UPS or autophagy degradation. The pathological tau extracted from NFTs can be monomers, oligomers, and PHFs secreted into the extracellular space upon the impairment of the UPS or autophagy in neurons. Abbreviations: p-Tau, phosphorylated tau; CMA, chaperone-mediated autophagy; AD, Alzheimer’s disease; NFTs, neurofibrillary tangles; VCP, valosin-containing protein; HSP70, heat shock protein 70, UPS, ubiquitin–proteasome system; and PHFs, paired helical filaments.
Figure 3
Figure 3
Molecular chaperones regulate tau degradation and stability via ubiquitination. (A) The 26S proteasomal degradation of tau. In AD, MT-bound tau can be phosphorylated by various kinases such as PKA, CaMKII, GSK-3β, and Cdk-5, causing tau to detach from MT (1). Then, aggregation-prone phosphorylated tau is recognized by HSP70/Hsc70 and its cochaperone BAG-1 to assist K48-linked polyubiquitination by the E3-ubiquitin ligase CHIP and E2-ubiquitin-conjugating UbcH5B protein complex (2). BAG-1 functions as a nucleotide exchange factor to release the misfolded and ubiquitinated tau from chaperones (3). The 26S proteasome consists of the inner catalytic core 20S proteasome and the outer regulatory 19S proteasome subunits, which recognize the ubiquitinated tau through binding to its ubiquitin chains and immediately unfold and deubiquitinate before entering into the 20S proteasome for tau degradation. The ubiquitinated tau substrate can be (4a) folded, (4b) phosphorylated and folded, and (4c) phosphorylated and unfolded. The non-ubiquitinated tau, including phosphorylated and non-phosphorylated folded tau, unfolded phosphorylated tau, and K63-linked polyubiquitinated tau, are not substrates for the 26S proteasomal degradation (5). (B) HSP90-FKBP51 regulates tau oligomerization. During in vitro conditions, HSP90 binds to paper-clip conformers of tau and promotes their oligomerization, which involves MTBRs (1). During in vivo conditions, HSP90 binds to its co-chaperone FKBP51 and enhances tau oligomerization (2), but this interaction does not allow transition into Thioflavin-T positive fibrillar tau (3). The HSP90-FKBP51 complex synergistically inhibits 20S proteasome-mediated degradation of tau (3), leading to the accumulation of phosphorylated tau (pT231) and toxic tau oligomers (T22 positive oligomers) (4). Tau oligomers can be stabilized by K63-linked polyubiquitin chains, which cannot be degraded by the 26S proteasome (5) unless it obtains K48-linked ubiquitin as a hybrid K63/K48-linked ubiquitination. Abbreviations: Ub, ubiquitin; CHIP, C-terminus of Hsc70-interacting protein; HSP70, heat shock protein 70; BAG-1, BCL2 Associated Athanogene-1; UbcH5B, ubiquitin-conjugating enzyme E2D 2; ATP, adenosine triphosphate; ADP, adenosine diphosphate; Pi, inorganic phosphate; HSP90, heat shock protein 90 kDa; FKBP51, FK506 binding protein 51 kDa; pT231, phosphorylated Tau at threonine 231; T22, tau oligomer specific antibody; and MTBRs, microtubule-binding repeats.
Figure 4
Figure 4
Chaperone-mediated autophagy (CMA) degradation of tau. The molecular chaperone Hsc70 binds to CMA motifs in tau and eventually interacts with the lysosome-associated membrane protein 2A (LAMP2A), which oligomerizes to form a channel-like structure to deliver tau along with Hsc70 into the lumen of the lysosome for degradation. Hsc70 stays with tau until the proteases digest tau. If not, tau gets aggregated in an acidic environment, leading to the generation of amyloidogenic tau fragments. The CMA can degrade tau if the CMA motifs can be easily accessible in either folded or unfolded tau. Acetylated tau is not a substrate of CMA, and it can eventually obtain ubiquitin chains for either autophagy or 26S proteasomal degradation. Abbreviations: HSP70, heat shock protein 70; Hsc70, heat shock cognate 71 kDa protein; CHIP, C-terminus of Hsc70-interacting protein; UPS, ubiquitin–proteasome system; CMA, chaperone-mediated autophagy; LAMP2A, lysosome-associated membrane protein 2A; and Ub, ubiquitin.
Figure 5
Figure 5
Autophagy degradation of tau. (A) Macroautophagy (autophagy) can degrade ubiquitinated non-aggregates or aggregates of tau upon the impairment of the ubiquitin–proteasome system (UPS). An autophagy receptor p62 (SQSTM1) recognizes polyubiquitinated tau as an autophagy cargo and interacts with LC3 (ATG8), which is lipidated with phosphatidylethanolamine (PE) to anchor cargo at the inner leaflet of the lipid bilayer for phagophore membrane expansion. Autophagosomes formed against tau can fuse to lysosomes for tau degradation, which is known as macroautophagy (autophagy). (B) Aggrephagy degradation of tau aggregates. Hyperubiquitinated tau aggregates within the aqueous phase are recognized by the p62 receptor initially and subsequently recruit other SQSTM1-like receptors (SLRs), including the next to BRCA1 gene 1 protein (NBR1) and Tax1 binding protein 1 (TAX1PB1) via their ubiquitin-binding domain (UBA). Tau aggregates are condensed via liquid–liquid phase separation (LLPS) (1) and recruit autophagy regulatory proteins, including LC3, for phagophore membrane expansion for liquid aggrephagy-mediated clearance of tau aggregates (2). However, some unknown factor(s) impair autophagosome formation or autophagosome maturation with the lysosome, leading to the formation of membrane-less solid aggregates of NFTs, which can be differentially marked with various linkage-specific ubiquitin chains (3). The molecular chaperone aggrephagy receptor chaperonin containing TCP1 subunit 2 (CCT2) can recognize solid protein aggregates via its apical domain for solid aggrephagy-mediated clearance of tau aggregates with or without ubiquitin chains (4a). The ubiquitin chaperone valosin-containing protein (VCP)/p97 ATPase extract ubiquitinated tau aggregates (K48/K6, K48/K11, or K48/K63 hybrid ubiquitin chains) for either autophagy or UPS-mediated degradation (4b). However, pathological tau, including monomers, oligomers (K63-linked or K48/K63-linked hybrid ubiquitin chains), and PHFs, are secreted into the extracellular space upon the impairment of autophagy or UPS. NFTs are marked with M1-linked linear ubiquitin chains for NF-κB associated inflammatory signaling activation in AD brains. Abbreviations: Ub, ubiquitin; LC3-PE, phosphatidylethanolamine conjugated to C-terminus of microtubule-associated protein 1 light chain 3; UPS, ubiquitin–proteasome system; HSP70, heat shock protein 70; and NFTs, neurofibrillary tangles.
Figure 6
Figure 6
Proteotoxic stress drives cellular senescence in AD. Pathological tau and Aβ drive proteotoxic stress in neurons by impairing the UPS and autophagy, causing an accumulation of intracellular NFTs and extracellular Aβ plaques in AD brains. Degenerating neurons secrete pathological tau into the extracellular space, where healthy neurons, microglia, astrocytes, OPC, and OL can endocytose/phagocytose tau for clearance. However, secreted tau species, including monomers, oligomers, and PHFs, are seeding competent, which propagates tau pathology in neurons and mature OL. Degenerating neuronal dendrites can secrete CSF1 and IL-34 that induce replicative senescence in microglia associated with the extracellular Aβ plaques (1). Pathological tau induces proteotoxic stress-driven senescence in microglia upon proteostasis impairment (2). Endocytosed tau oligomers can induce senescence in astrocytes and lead to the secretion of HMGB1 into the extracellular space. Senescent astrocytes may impair glutamate homeostasis, leading to glutamate excitotoxicity in AD (3). Protein aggregates (PAs) and senescent astrocytes secreted HMGB1 can also impair the differentiation of OPC into mature OL, causing demyelination of neurons (4). Abbreviations: CSF1, colony-stimulating factor 1; IL-34, interleukin-34; PAs, protein aggregates; Aβ, amyloid beta; NFT, neurofibrillary tangle; OPC, oligodendrocyte progenitor cell; OL, oligodendrocyte; and HMGB1, high mobility group box 1.
Figure 7
Figure 7
Senescent astrocytes impair glutamate homeostasis in AD. Senescence in astrocytes is induced by AD-associated tau oligomers/Aβ1–42 peptide. Senescent astrocytes show characteristics of increased GFAP, p16, HMGB1, APOE, and connexin-43 (CX43), and decreased EAAT 1/2, Kir4.1, and AQP4 levels upon exposure to ionizing radiation (1). The glutamate–glutamine cycle is essential for proper neuronal excitation by which presynaptic neurons release glutamate at the synaptic zone. The SNARE complex regulates the fusion of glutamate vesicles with the presynaptic membrane to release glutamate (2). AMPAR/NMDAR binds to glutamate, eventually allowing an influx of Na+ and Ca2+ ions to induce an action potential at the postsynaptic neurons (3). Excessively released glutamate is taken up by astrocytes via EAAT 1/2 channels, where glutamine synthase (GS) converts glutamate into glutamine and is exported into neurons for the next cycle of neuron excitation by which regulated neurotransmission is maintained (4). In senescent astrocytes, the EAAT 1/2 level is decreased, causing the accumulation of glutamate in the synaptic cleft and extrasynaptic regions, which leads to excitotoxicity (5), impairing AD memory retrieval. Abbreviations: HMGB1, high mobility group box 1; GFAP, glial fibrillary acidic protein; p16, cyclin-dependent kinase inhibitor 2A; K+, potassium ion; Kir4.1, inwardly rectifying potassium channel 4.1; AQP4, aquaporin-4; GS, glutamine synthase; EAAT 1/2, excitatory amino acid transporters 1/2; APOE, apolipoprotein E; CX43, connexin-43; Gln, glutamine; Glu, glutamic acid; VGLUT, vesicular glutamate transporter; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; mGluR, metabotropic glutamate receptor; Na+, sodium ion; Ca+, calcium ion; AMPAR, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; and NMDAR, N-methyl-D-aspartate receptor.
Figure 8
Figure 8
Nuclear remodeling and TOR-autophagy spatial coupling compartment (TASCC) regulate senescence cell survival. Senescent-inducing factors regulate the translocation of nuclear transmembrane protein lamin B receptor (LBR) into the cytoplasm for proteasomal degradation or are, perhaps, degraded by nucleophagy (1). Chronic inhibition of the UPS or autophagy induces senescence by remodeling the nucleus for relaxed gene expression. The oncogene RAS-induced autophagy, but not by mTOR inhibition or starvation-induced autophagy, regulates the degradation of lamin B1 (LMNB1), causing oncogene-induced senescence (2). In senescent cells, nuclear autophagy (nucleophagy) degrades LMNB1 nuclear blebs (2) and SIRT1 (3) by interacting with ubiquitin-like LC3B to remodel the nuclear membrane and chromatin for relaxed gene expression (4). Senescent cells import the proteasome subunit proteins into the nucleus to assemble the 26S proteasome and eventually form senescence-associated nuclear proteasome foci (SANP) by actively recruiting VCP/p97 ATPase and RAD23 to degrade unknown nuclear proteins (5). Senescent cells enhance the nuclear translocation of active dephosphorylated TFEB (6) and NF-κB (7) for increased lysosome biogenesis and senescence-associated immune response gene expression (8), respectively. In RAS-induced senescence, the trans-Golgi network (TGN) provides a novel compartment, TOR-autophagy spatial coupling compartment (TASCC), for accelerated mTOR and autophagy activities (9), which is essential for senescent cell survival. An alternative autophagy, LC3-independent Golgi-membrane-associated degradation (GOMED) pathway is activated upon the impairment of the Golgi to plasma membrane trafficking that eventually triggers extensive remodeling of the nuclear membrane leading to the terminal cell atrophy (10). Abbreviations: LBR, lamin B receptor; LMNB1, lamin B1; SIRT1, sirtuin 1; LC3B, microtubule-associated protein 1 light chain 3 beta; TFEB, transcription factor EB; TGN, trans-Golgi network; SASP, senescence-associated secretory phenotype; NF-κB, nuclear factor kappa B; IL, interleukin; TNFα, tumor necrosis factor alpha; ER, endoplasmic reticulum; RAD23B, UV excision repair protein RAD23 homolog B; VCP, valosin-containing protein; mTOR, mammalian _target of rapamycin; RAS, rat sarcoma virus; TASCC, TOR-autophagy spatial coupling compartment; GOMED, Golgi-membrane-associated degradation; and SANP, senescence-associated nuclear proteasome foci.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Wang Y., Mandelkow E. Tau in physiology and pathology. Nat. Rev. Neurosci. 2016;17:5–21. doi: 10.1038/nrn.2015.1. - DOI - PubMed
    1. LoPresti P. Tau in Oligodendrocytes Takes Neurons in Sickness and in Health. Int. J. Mol. Sci. 2018;19:2408. doi: 10.3390/ijms19082408. - DOI - PMC - PubMed
    1. Poorkaj P., Bird T.D., Wijsman E., Nemens E., Garruto R.M., Anderson L., Andreadis A., Wiederholt W.C., Raskind M., Schellenberg G.D. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 1998;43:815–825. doi: 10.1002/ana.410430617. - DOI - PubMed
    1. Ghetti B., Oblak A.L., Boeve B.F., Johnson K.A., Dickerson B.C., Goedert M. Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: A chameleon for neuropathology and neuroimaging. Neuropathol. Appl. Neurobiol. 2015;41:24–46. doi: 10.1111/nan.12213. - DOI - PMC - PubMed
    1. Zhang Y., Wu K.-M., Yang L., Dong Q., Yu J.-T. Tauopathies: New perspectives and challenges. Mol. Neurodegener. 2022;17:28. doi: 10.1186/s13024-022-00533-z. - DOI - PMC - PubMed

Substances

LinkOut - more resources

  NODES
twitter 2