PubMed: 30126037

Tau protein aggregation is associated with cellular senescence in the brain.
Aging cell
Sickora KR | Orr ME | Thompson CS | Baeuerle E | Valentine JM | Shen Q | Musi N

Evidence c9d080f2a4

In 15-month-old mice with heavy Abeta deposition and phosphorylated tau, but lacking NFT pathology (Orr et al., 2014), Cdkn2a expression was not elevated (Figure 4e). These data indicate that Cdkn2a expression was neither a response to general protein accumulation, nor to pre-NFT tau pathology, but instead required the presence of NFTs

Evidence f90c96f77d

Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss (Arriagada et al., 1992), yet mechanisms mediating tau toxicity are poorly understood

Evidence 1ca60603cf

NFT containing neurons upregulated genes involved in cell survival and viability, inflammation, cell cycle progression and molecular transport and downregulated apoptosis, necrosis and cell death pathways (Figure 1a). NFkB, a pro-survival master transcriptional regulator of inflammation, was the highest predicted upstream regulator of the NFT-gene expression profile. In agreement with inflammatory activation, other predicted upstream regulators included IFNG, TNF, TLR4, IL1B and CXCL1 (Figure 1b)

Evidence 452fd46da7

Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice

Evidence 5ce421d221

Consistent with NFTs from human AD, mouse NFTs also caused significant activation scores for IFNG, TNF, IL-1B, as well as enrichment in other senescence associated JAK, STAT, CDKN2A and BCL2 predicted upstream regulators (Figure 1c) indicating translational relevance for using tauNFT mice to explore our hypothesis

Evidence 8220defaa1

Cdkn2a gene expression increased significantly during this age interval, and at 28 months of age tauWT Cdkn2a expression was similar to that of 16-month-old tauNFT mice (Figure 4c)

Evidence 1c22f25a14

Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration

Evidence c43cd42c8a

Similarly, elevated expression of the cyclin dependent kinase inhibitor 2a, Cdkn2a, is one of the most robust markers of cellular senescence, and its protein product, p16INK4A, co-localizes with NFTs in human AD (Arendt et al., 1996)

Evidence 3ef1fdb135

Consistent with the results from transgenic mice, CDKN2A was upregulated in PSP brains (P = 0.0415, Figure 4g) and expression correlated with NFT deposition, specifically in the parietal lobe (ANOVA, P = 0.0008; Kendall’s Tau rank correlation P = 0.059, Figure 4h)

Evidence e27b10e7a0

Collectively, these findings led us to conclude that NFTs were directly linked to senescence-associated Cdkn2a upregulation, which in turn was a strong predictor of neurodegeneration and cognitive decline

Evidence ff4be5ab78

We found a significant genotype main effect for oxygen flux in both cortex and hippocampus, indicating that global respiratory capacity was impaired in NFT containing brain regions (P < 0.0001; Figure 3), an effect primarily driven by CI+CII respiration coupled to ATP production (cortex: P = 0.0034; hippocampus: P = 0.0215; Figure 2g and h, respectively), and uncoupled or maximum respiratory capacity (cortex: P = 0.0248; hippocampus: P = 0.0261; Figure 3g and h, respectively)

Evidence eae8cf1dae

NFTs are highly correlated with the rate of ventricular enlargement, an indicator of brain atrophy and hallmark of AD pathology (Silbert et al., 2003)

Evidence 263ff302ab

Further, SA beta-gal reactive cells were observed even in very young mice (1-month-old) and the number of SA beta-gal reactive cells was positively correlated with brain mass (R2: 0.4852, P = 0.0039 Figure S3)

Evidence 57a6c2a3cf

Citrate synthase activity is a surrogate marker of total mitochondrial content/mass, and was similar across genotypes and brain regions (Figure 3i) suggesting that the defects in cellular respiration were due to altered mitochondrial quality, not content/mass

Evidence 3750c95a2a

Transcriptomic analyses of NFT-containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction

Evidence 6884c73761

This complex stress response induces a near permanent cell cycle arrest, adaptations to maintain survival, cellular remodeling, metabolic dysfunction and disruption to surrounding tissue to the secretion of toxic molecules (Childs et al., 2016)

Evidence e6998aaab8

NFkB regulates the pro-survival, pro-inflammatory SASP gene expression profile characteristic of cellular senescence (Salminen & Kaarniranta, 2011)

Evidence 2b241a4936

Tau transgenic mice with late stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss and ventricular enlargement

Evidence a0ea675a42

Experimental data from various studies indicate that tau pathology may be associated with cellular senescence, a fundamental aging mechanism shown to contribute to several chronic diseases (recent review Kirkland and Tchkonia, 2017)

Evidence d89bf1c9eb

Senescence-inducing stressors often inflict DNA-damage that drives production of the SASP (Rodier et al., 2009)

Evidence 72ee914b50

The cell cycle protein p21, encoded by Cdkn1a, is upregulated in many senescent cell types and has been associated with DNA damage during neuronal aging (Jurk et al., 2012)

Evidence 06071c4a2f

Mitochondrial dysfunction is obligatory for SASP production and cellular senescence (Correia-Melo et al., 2016; Hutter et al., 2004)

Evidence 089db82ad7

Aberrant cerebral blood flow is a functional defect that occurs in AD and tauNFT mice, and is closely associated with cognitive impairment (Wells et al., 2015)

Evidence c7fa0fb320

Consistent with senescent cell removal, intermittent DQ treatment significantly reduced the number of NFT-containing cortical neurons (P < 0.0001, 5% reduction; Figure 5a,b)

Evidence 9d9802bc22

The DQ-dependent reduction in cortical NFTs corresponded with decreased ventricular volume pathology (28% decrease, P = 0.05, Figure 5d, f) and a reduction in cortical brain atrophy (compared to controls: P = 0.0092 and P = 0.0274, vehicle and DQ, respectively; Figure S5a)

Evidence 0e55422078

The astrocyte protein GFAP was unchanged, while microglia Iba1 expression was elevated (Iba1: 40%, P = 0.0013; Figure S6b-d) suggesting that DQ-mediated neuroprotection and decreased SASP was not derived from a reduction in pro-inflammatory glia (astrocytes or microglia) but instead associated with fewer NFT-containing neurons

Evidence 810d458008

Relative to the existing neuronal population at this advanced age, gene expression of the NFT-associated senescence gene array was reduced by DQ (P = 0.0006; Figure S6a)

Evidence 10f4227c23

However, tauNFT-Mapt0/0 mice treated with DQ did not display WMH volumes statistically different than control mice (P = 0.2458; Figure S5b, c)

Evidence 985531e6d6

DQ improved cerebral blood flow in tauNFT Mapt0/0 mice such that cerebral blood flow was no longer statistically different from controls (Figure S5d, e)

Evidence 3fa6183730

DQ-treated mice expressed significantly higher levels of neuronal proteins (NeuN: 25%, synaptophysin: 40.8%; PSD95: 38.5%; P < 0.05; Figure 5f-i)

Evidence a817a69bb5

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others

Evidence 4bc1381721

Further, when plotted against brain weight, Cdkn2a expression was a strong predictor of brain atrophy across mouse lines (P < 0.0001, R2 = 0.5615; Figure 4f)

Evidence 18d5af744b

TauNFT mouse brains displayed significantly elevated histone γ-H2ax, a sensitive marker of both double-stranded DNA breaks and cellular senescence (Sedelnikova et al., 2004) (P = 0.0056; Figure 1d-e)

Evidence 1495e4aa74

However, genetically ablating endogenous mouse tau (microtubule associated protein tau, Mapt) reduces NFT pathology and neurodegeneration in tauNFT mice (tauNFT-Mapt0/0) (Wegmann et al., 2015)

Evidence 0f8d65f693

The reduced tau pathology corresponded with 60% lower Cdkn2a expression (P = 0.0041, Figure 4a), decreased SASP (Figure S4) and decreased brain atrophy (tauNFT-Mapt0/0: 0.4058 ± 0.009 versus age-matched tauNFT Maptwt/wt: 0.3451 ± 0.0116; 17.5% difference, P = 0.0143, Figure 4b)

Evidence dedeae1276

TauNFT brains expressed 3-fold higher Cdkn1a than control mice (P = 0.0178, Figure 1f), which was replicated in a separate mouse cohort (P = 0.0086, Figure S1f)

Evidence 8091e10067

Moreover, Cdkn2a was expressed at levels 2.7- and 2.6-fold higher in tauNFT than CTL and tauWT, respectively (P = 0.0303 and P = 0.0352, respectively; Figure 1g); this effect was replicated in an independent mouse cohort (P = 0.0016, Figure S1g)

Evidence af290ffc7d

Consistent with the transcriptomic profile in human NFT-bearing neurons and mouse brain tissue (Figure 1a-c), SASP genes were found to be upregulated in tauNFT brains, i.e., Il1b was 4- and 2-fold higher than CTL and tauWT, respectively; and Cxcl1 was 4-fold higher than both control genotypes; Tnfa was 13- and 8-fold higher than CTL and tauWT, respectively; Tlr4 was 3-fold higher than both control genotypes (Figure 2a-d)

Evidence 068a3e0907

Consistent with NFkB pathway activation and the SASP profile, nuclear localized NFkB p65 was significantly increased in tauNFT brains (Figure 2e-f)

Evidence e86f79b6d7

Examination of the gene that codes for the hydrolase enzyme, galactosidase beta 1 (Glb1), revealed that tauNFT mice expressed higher Glb1 gene expression than controls (Figure S3)

Evidence 275f3809ce

TauNFT mice develop aggressive tauopathy with NFT formation in early life, and show a senescence-associated transcriptomic profile with NFT onset (Figure 1c)

Evidence dfa58e54c0

In brain tissue with tau pathology, cerebral blood flow was elevated in tauNFT Mapt0/0 vehicle-treated mice (21% whole brain, P = 0.045; cortex, 48.7%, P = 0.051, Figure S5d, e), and consistent with previous reports of tauNFT mice on a Mapt+/+ background (Wells et al., 2015)

Evidence 4ba357d358

WMH is driven by cerebral small vessel disease, which causes chronic ischemia and increased risk of cognitive decline and dementia (reviewed, (Prins & Scheltens, 2015))

Evidence 02ac4f741d

PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991)


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