A Mutant Variant of E2F4 Triggers Multifactorial Therapeutic Effects in 5xFAD Mice

López-Sánchez, Noelia; Ramón-Landreau, Morgan; Trujillo, Cristina; Garrido-García, Alberto; Frade, José Marı́a

doi:10.1007/s12035-022-02764-z

Cited by 6 publications

(49 citation statements)

References 98 publications

(156 reference statements)

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“…Recent studies in our laboratory have confirmed that the expression in neurons of both mouse and human E2F4DN prevents neuronal tetraploidy in 5xFAD mice [12]. Moreover, as expected from a multifactorial factor, neuronal expression of E2F4DN was able to mitigate other processes that become affected in AD such as neuroinflammation, A peptide proteostasis, and body weight loss [12], a known somatic alteration associated with AD [152].…”

Section: The Connection Of E2f4 With Admentioning

confidence: 69%

“…As observed in this cell line, as well as in mouse embryonic stem cells, E2F4 may activate or repress gene expression, according to its interaction partner [27,19]. Interestingly, E2F4 malfunction has been linked to cognitive impairment [94] as well as the ethiopathology of neurodegenerative diseases such as Alzheimer's disease (AD) [11,12]. This is consistent with a recent study that proposes E2F4 as a major regulator of most AD-specific gene networks [95], and with other bioinformatics-based studies suggesting that E2F4 participates in this disease [147][148][149].…”

Section: The Connection Of E2f4 With Admentioning

confidence: 80%

“…We have demonstrated in developing chick neurons that the expression of a dominant negative variant of chick E2F4 (E2F4DN) containing Ala substitutions in the Thr residues ortologous to T248 and T250 can prevent cell cycle re-entry in these cells and the subsequent DNA duplication that results in somatic neuronal tetraploidy [13]. Recent studies in our laboratory have confirmed that the expression in neurons of both mouse and human E2F4DN prevents neuronal tetraploidy in 5xFAD mice [12]. Moreover, as expected from a multifactorial factor, neuronal expression of E2F4DN was able to mitigate other processes that become affected in AD such as neuroinflammation, A peptide proteostasis, and body weight loss [12], a known somatic alteration associated with AD [152].…”

Section: The Connection Of E2f4 With Admentioning

confidence: 96%

“…Other authors have confirmed the phosphorylation of T14, S218, S244, T248 and S381 in human E2F4 [19], of S218, T224, T249 and S384 in mouse E2F4 [19] and the ortologue of T248/T250 (T261/T263) in chicken E2F4 [13]. In addition, phosphoryation of E2F4 in T249 has been observed in mouse brain extracts using a phosphosite-specific antibody [11] and indirect evidence for the phosphorylation of T248 in human brain was obtained using a proximity ligation assay with anti-E2F4 and anti-phosphoThreonine antibodies [12]. Hsu and collaborators [19] also found evidence of phosphorylation in S16, Y139, S185, S187, S220, S223 and Y389 from human E2F4 and in S75, Y139, T153, S223, S240, T266, Y392 AND Y394 mouse E2F4.…”

Section: Regulation Of E2f4 Function By Chemical Modificationsmentioning

confidence: 99%

“…Interestingly, E2F4 can also play other important roles in cellular physiology, including cell and tissue homeostasis and tissue regeneration [7,8,[10][11][12]. Therefore, E2F4 can be considered as a multifactorial factor with an important impact in neuronal welfare and brain homeostasis [11,12], suggesting that it may be a promising candidate target for neurodegenerative diseases and brain aging.…”

Section: Introductionmentioning

confidence: 99%

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E2F4DN Transgenic Mice: A Tool for the Evaluation of E2F4 as a Therapeutic Target in Neuropathology and Brain Aging

Ramón-Landreau¹,

Sánchez‐Puelles²,

López-Sánchez³

et al. 2022

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E2F4 was initially described as a transcription factor with a key function in the regulation of cell quiescence. Nevertheless, a number of recent studies have established that E2F4 can also play a relevant role in cell and tissue homeostasis as well as tissue regeneration. For these non-canonical functions, E2F4 can also act in the cytoplasm, where it is able to interact with many homeostatic and synaptic regulators. Since E2F4 is expressed in the nervous system, it may fulfill a crucial role in brain function and homeostasis, being a promising multifactorial target for neurodegenerative diseases and brain aging. The regulation of E2F4 is complex as it can be chemically modified through acetylation, from which we present evidence in the brain, as well as methylation, and phosphorylation. The phosphorylation of E2F4 within a conserved threonine motif induces cell cycle re-entry in neurons, while a dominant negative form of E2F4 (E2F4DN), in which the conserved threonines have been substituted by alanines, has been shown to act as a multifactorial therapeutic agent for Alzheimer’s disease (AD). We have generated transgenic mice neuronally expressing E2F4DN. We have recently shown using this mouse strain that expression of E2F4DN in 5xFAD mice, a known murine model of AD, improved cognitive function, reduced neuronal tetraploidization, and induced a transcriptional program consistent with modulation of amyloid-beta (Abeta) peptide proteostasis and brain homeostasis recovery. 5xFAD/E2F4DN mice also showed reduced microgliosis and astrogliosis in both cerebral cortex and hippocampus at 3-6 months of age. Here we have analyzed the immune response in 1 year-old 5xFAD/E2F4DN mice, concluding that reduced microgliosis and astrogliosis is maintained at this late stage. In addition, the expression of E2F4DN also reduced age-associated microgliosis in wild-type mice, thus stressing its role as a brain homeostatic agent. We conclude that E2F4DN transgenic mice represent a promising tool for the evaluation of E2F4 as a therapeutic target in neuropathology and brain aging.

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Section: The Connection Of E2f4 With Admentioning

confidence: 69%

Section: The Connection Of E2f4 With Admentioning

confidence: 80%

Section: The Connection Of E2f4 With Admentioning

confidence: 96%

Section: Regulation Of E2f4 Function By Chemical Modificationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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E2F4DN Transgenic Mice: A Tool for the Evaluation of E2F4 as a Therapeutic Target in Neuropathology and Brain Aging

Ramón-Landreau¹,

Sánchez‐Puelles²,

López-Sánchez³

et al. 2022

Preprint

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Somatic mutations in Alzheimer-associated tetraploid neurons

López-Sánchez,

Rábano,

Frade

2024

Preprint

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An early pathological process affecting the brain of Alzheimers disease (AD) is the reactivation of the cell cycle in neurons followed by somatic neuronal tetraploidization (NT). NT also increases with age, and ageing has been shown to correlate with the accumulation of DNA somatic mutations. In this study, we have evaluated the presence of somatic mutations including single nucleotide variants (SNVs) and indels in genomic DNA from tetraploid neurons obtained from the parietal cortex of AD patients, compared with diploid neurons from control individuals and AD patients. Here we show that, in contrast to somatic indels, the proportion of somatic SNVs (sSNVs) significantly increases in the exome of tetraploid neurons, having increased levels of T to C (A to G) transitions, a type of mutation that is associated with oxidative stress. This finding correlates with the over-representation of sSNVs in genes involved in oxidative stress response and DNA repair, suggesting that these alterations exacerbate oxidative DNA damage in tetraploid neurons. sSNVs affecting cancer-related (CR) genes showed a greater molecular pathogenicity score compared with those from a random sample of genes. We propose that neuronal tetraploidy is stochastically triggered through a CR mechanism in neurons whose DNA repair genes become mutated in an oxidative stress scenario. This mechanism likely participates in the etiology of AD.

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Comparative gene regulatory networks modulatingAPOEexpression in microglia and astrocytes

Brase,

Yu,

McDade

et al. 2024

Preprint

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Background: Single-cell technologies have unveiled various transcriptional states in different brain cell types. Transcription factors (TFs) regulate the expression of related gene sets, thereby controlling these diverse expression states. Apolipoprotein E (APOE), a pivotal risk-modifying gene in Alzheimer's disease (AD), is expressed in specific glial transcriptional states associated with AD. However, it is still unknown whether the upstream regulatory programs that modulate its expression are shared across brain cell types or specific to microglia and astrocytes. Methods: We used pySCENIC to construct state-specific gene regulatory networks (GRNs) for resting and activated cell states within microglia and astrocytes based on single-nucleus RNA sequencing data from AD patients' cortices from the Knight ADRC-DIAN cohort. We then identified replicating TF using data from the ROSMAP cohort. We identified sets of genes co-regulated with APOE by clustering the GRN target genes and identifying genes differentially expressed after the virtual knockout of TFs regulating APOE. We performed enrichment analyses on these gene sets and evaluated their overlap with genes found in AD GWAS loci. Results: We identified an average of 96 replicating regulators for each microglial and astrocyte cell state. Our analysis identified the CEBP, JUN, FOS, and FOXO TF families as key regulators of microglial APOE expression. The steroid/thyroid hormone receptor families, including the THR TF family, consistently regulated APOE across astrocyte states, while CEBP and JUN TF families were also involved in resting astrocytes. AD GWAS-associated genes (PGRN, FCGR3A, CTSH, ABCA1, MARCKS, CTSB, SQSTM1, TSC22D4, FCER1G, and HLA genes) are co-regulated with APOE. We also uncovered that APOE-regulating TFs were linked to circadian rhythm (BHLHE40, DBP, XBP1, CREM, SREBF1, FOXO3, and NR2F1). Conclusions: Our findings reveal a novel perspective on the transcriptional regulation of APOE in the human brain. We found a comprehensive and cell-type-specific regulatory landscape for APOE, revealing distinct and shared regulatory mechanisms across microglia and astrocytes, underscoring the complexity of APOE regulation. APOE-co-regulated genes might also affect AD risk. Furthermore, our study uncovers a potential link between circadian rhythm disruption and APOE regulation, shedding new light on the pathogenesis of AD.

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A Mutant Variant of E2F4 Triggers Multifactorial Therapeutic Effects in 5xFAD Mice

Cited by 6 publications

References 98 publications

E2F4DN Transgenic Mice: A Tool for the Evaluation of E2F4 as a Therapeutic Target in Neuropathology and Brain Aging

E2F4DN Transgenic Mice: A Tool for the Evaluation of E2F4 as a Therapeutic Target in Neuropathology and Brain Aging

Somatic mutations in Alzheimer-associated tetraploid neurons

Comparative gene regulatory networks modulatingAPOEexpression in microglia and astrocytes

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