Lulu Jiang

The aggregation of the microtubule-associated protein tau into oligomeric complexes is strongly correlated with the onset and progression of neurodegeneration in Alzheimer’s disease (AD). Increasing evidence implicates nuclear membrane disruption in AD and related tauopathies; however, whether this is a cause or consequence of neurodegeneration remains unresolved. Here, we show that nuclear lamina disruption emerges at the early Braak stages, coinciding with the initial formation of pathological tau aggregates in post-mortem AD brain tissue. Using the tauopathy mouse model (P301S PS19), we demonstrate that oligomeric tau (oTau) directly binds to the Lamin B Receptor (LBR), inducing nuclear envelope invaginations as revealed by electron microscopy. These structural alterations are accompanied by chromatin remodeling and gene expression dysregulation. To dissect the underlying mechanism, we employed a light-inducible OptoTau system (4R1N Tau::mCherry::Cry2Olig) in human iPSC-derived neurons, enabling real-time visualization of tau aggregation dynamics. This system revealed selective recruitment of oTau to the nuclear envelope and direct interactions with LBR and Lamin B2, leading to nuclear deformation and activation of the protein translational stress response. Together, these findings identify nuclear membrane disruption as an early and potentially causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization, nuclear stress, and chromatin remodeling. Targeting nuclear destabilization may offer new therapeutic avenues for mitigating AD pathogenesis.

ER-associated degradation (ERAD) targets misfolded proteins in the endoplasmic reticulum (ER) for proteasomal degradation. Mutations in its most conserved branch involving the SEL1L-HRD1 complex cause ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI), characterized by developmental delay, microcephaly, and locomotor dysfunction. Its most severe form, ENDI with agammaglobulinemia (ENDI-A), results from a bi-allelic SEL1L-Cys141Tyr (C141Y) mutation within its fibronectin II (FNII) domain and currently lacks effective treatment. Here, we find that knock-in mouse models carrying the C141Y mutation are unexpectedly rescued via increased use of an alternative splice donor within exon 4 leading to bypass of the mutant FNII-encoding region. The resulting SEL1L variant restores ERAD activity, and rescues perinatal lethality, B cell deficiency, and neurodevelopmental defects. Leveraging this mechanism, we demonstrate that antisense oligonucleotide-mediated exon skipping in patient-derived fibroblasts generates a truncated yet functional SEL1L protein that fully restores ERAD function and ER proteostasis. These results establish RNA splicing-modulation as a viable therapeutic strategy for ERAD deficiency and broaden the clinical potential of exon-skipping therapy to diseases of protein misfolding.

Summary Paragraph: Tau misfolding and aggregation are central to cognitive decline in Alzheimer’s disease and related neurodegenerative disorders ^1–3 . Although soluble tau oligomers are implicated as primary toxic species ^4–6 , the structural and compositional determinants of their toxicity remain inaccessible at the single oligomer level. Here we introduce infrared absorbance-modulated evanescent scattering (IR-AMES), a label-free single-molecule spectroscopic imaging approach that photothermally encodes mid-infrared vibrational fingerprints into evanescent scattering from individual biomolecular assemblies under native aqueous conditions. Applying IR-AMES to recombinant human tau resolves random-coil-dominated monomers and captures the emergence of structurally heterogeneous oligomers. Analysis of tau oligomers from postmortem Alzheimer’s disease brains uncovers enrichment of antiparallel β-sheet structures and RNA components, features that are largely obscured in ensemble-averaged measurements. Using lipid nanodiscs as a defined membrane mimic, we further show that pathological tau oligomers exhibit enhanced interactions with anionic membranes. Together, these findings establish a link between structure and neurotoxicity of tau oligomers, and position IR-AMES as a platform for uncovering structure–function relationships in complex biomolecular assemblies.

The nucleus, as the largest organelle within the cell, serves as the central hub for storing, replicating, and transcribing genetic information, thereby orchestrating vital cellular processes. In eukaryotic cells, the nuclear membrane is composed of several structural components: the outer and inner nuclear membranes, the nuclear pore complexes, and the underlying nuclear lamina, which together preserve the stability of the intracellular environment. Neurodegenerative disorders, such as Alzheimer’s disease and related dementias, are characterized by the gradual degeneration and loss of neuronal structure and function in the central nervous system. Growing evidence suggests that alterations in nuclear envelope architecture are closely associated with the onset and progression of these diseases. This article summarizes the information, focusing on the regulators of the cell nuclear membrane, as well as its pathophysiological processes and regulatory mechanisms in neurodegenerative diseases. Moreover, this paper discusses related research advances that provide novel insights into a deeper understanding of the nuclear membrane in disease progression and its potential as a therapeutic target.

Dysregulation of N6-methyladenosine (m6A) modification of RNA has emerged as a novel feature of Alzheimer’s disease (AD). Here, we investigate the relationship between m6A modification and AD pathology, and the therapeutic potential of modulating excessive m6A via its “writer” methyltransferase METTL3 in a humanized P301S tau transgenic mouse model of AD (PS19). We observed significantly elevated m6A levels in human post-mortem AD frontal cortex tissue compared to healthy controls, which positively correlated with hyperphosphorylated tau and amyloid-β (Aβ) deposition. These effects were recapitulated in the PS19 tau mice model of AD. Importantly, treatment of PS19 mice with the METTL3 inhibitor STM2457 reduced excessive m6A, alleviated tau pathology, and attenuated neurodegeneration. Behavioral assessments further demonstrated that STM2457-treated PS19 mice exhibited significantly improved learning and memory relative to untreated PS19 mice. Our results identify m6A as a critical contributor to AD pathogenesis and demonstrate that pharmacological inhibition of METTL3 represents a promising therapeutic strategy to improve cognition in AD.

The microtubule-associated protein tau aggregates into oligomeric complexes that highly correlate with Alzheimer’s disease (AD) progression. Increasing evidence suggests that nuclear membrane disruption occurs in AD and related tauopathies, but whether this is a cause or consequence of neurodegeneration remains unclear. Using the optogenetically inducible 4R1N Tau::mCherry::Cry2Olig (optoTau) system in iPSC-derived neurons, we demonstrate that tau oligomerization triggers nuclear rupture and nuclear membrane invagination. Pathological tau accumulates at sites of invagination, inducing structural abnormalities in the nuclear envelope and piercing into the nuclear space. These findings were confirmed in the humanized P301S tau (PS19) transgenic mouse model, where nuclear envelope disruption appeared as an early-onset event preceding neurodegeneration. Further validation in post-mortem AD brain tissues revealed nuclear lamina disruption correlating with pathological tau emergence in early-stage patients. Notably, electron microscopy shows that tau-induced nuclear invagination triggers global chromatin reorganization, potentially driving aberrant gene expression and protein translation associated with AD. These findings suggest that nuclear membrane disruption is an early and possibly causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization and nuclear stress. Further investigation into nuclear destabilization could inform clinical strategies for mitigating AD pathogenesis.

The study for the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular β-amyloid (Aβ) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APP^NL−G−F MAPT^P301S mouse that at 6 months of age exhibits robust Aβ plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of Aβ pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated Aβ accumulation. The APP^NL−G−F/MAPT^P301S mouse model also showed strong accumulation of N⁶-methyladenosine (m⁶A), which was recently shown to be elevated in the AD brain. M6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m⁶A from mRNA, respectively. Thus, the APP^NL−G−F/MAPT^P301S mouse recapitulates many features of AD pathology beginning at 6 months of aging.

The study for the pathophysiology study of Alzheimer’s disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular β-amyloid (Aβ) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APP ^NL-G-F MAPT ^P301S mouse that at 6 months of age exhibits robust Aβ plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of Aβ pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated Aβ accumulation. The APP ^NL-G-F /MAPT ^P301S mouse model also showed strong accumulation of N ⁶ -methyladenosine (m ⁶ A), which was recently shown to be elevated in the AD brain. M6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m ⁶ A from mRNA, respectively. Thus, the APP ^{NL- G-F} /MAPT ^P301S mouse recapitulates many features of AD pathology beginning at 6 months of aging.