Mauro Montalbano

Tau protein aggregates adopt distinct conformations across tauopathies, yet the protein interactions engaged by disease-specific polymorphs remain poorly characterized. Here, we demonstrate that conformationally distinct tau polymorphs associate with disease-specific interaction networks across Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Interactome profiling of tau aggregates from PBS- and sarkosyl-soluble brain fractions identified 493 high-confidence interactors exhibiting remarkable disease specificity. As an exploratory feature discovery machine learning classification discriminated against diseases using as few as four to six protein features. AD tau selectively engaged glycolytic enzymes, TCA cycle components, and glutamate/GABA cycling machinery, with the astrocytic transporter SLC1A2 showing 27-fold enrichment. PSP tau exhibited extensive interactor depletion alongside selective proteasome enrichment, whereas DLB tau associated with neurogenesis modulators while depleting neuroinflammatory mediators. Interaction patterns were corroborated by parallel reaction monitoring mass spectrometry and proximity ligation assays and corresponded to disease-specific post-translational modification profiles. These findings show that tau polymorph conformations are associated with disease-specific interaction networks, providing molecular insight into tauopathy heterogeneity.

There is a pressing need to develop novel strategies to ameliorate symptoms and slow the progression of Alzheimer’s disease. One of the hallmarks of Alzheimer’s disease is the high levels of tau protein, which can form toxic oligomers and characteristic neurofibrillary tangles in the brain. Antitau antibodies can potentially bind tau protein and reduce tau pathology. In order to elicit a powerful antitau antibody response, virus-like-particle bacteriophage Qβ-based conjugate vaccines were developed targeting the microtubule binding region of tau protein. The Qβ-tau vaccines were able to produce a strong antitau antibody response in not only wild-type mice but also in human tau transgenic mice and a llama. The levels of antibody induced were superior to those generated by a corresponding keyhole limpet hemocyanin-based tau conjugate mimicking the one vaccine that successfully completed phase 1/2 human clinical trials. The Qβ-tau vaccine significantly improved the cognitive functions of the immunized mice and reduced the levels of inflammatory cytokines and tau in the brains, suggesting its translational potential.

Neurodegenerative diseases are characterized by a loss of neuronal function and structure, often in a region‐specific manner. Multiple factors contribute to neuronal dysfunction and death, including pathogenic protein buildup, protein mislocalization, and inflammation. Despite extensive research, the common mechanisms driving neurodegeneration remain incompletely understood, partly because pathological processes affect interconnected cellular components such as the cytosol, cytoskeleton, and nucleus. Emerging evidence indicates that changes in nuclear structure and function are not simply secondary to cellular stress but play key roles in aging and neurodegenerative disease progression. This review explores important aspects of nuclear dysfunction, including alterations in nuclear architecture, chromatin organization, nucleocytoplasmic transport, DNA damage responses, and inflammatory signaling. It further discusses how these processes converge to increase neuronal vulnerability and may extend beyond normal aging to promote neurodegeneration. Overall, this review highlights nuclear dysfunction as a significant factor in neuronal impairment and underscores the need for therapies targeting nuclear integrity.

Breast cancer (BC) is a highly heterogeneous genetic disease, comprising several subtypes with distinct features that significantly influence prognosis and treatment outcomes. Among these subtypes, triple-negative breast cancer (TNBC) is particularly aggressive and makes it resistant to many standard therapies. Epigenetic mechanisms, including acetylation and deacetylation, are crucial in regulating gene expression and maintaining normal cellular functions and are closely associated with BC progression. In this context, the histone deacetylases sirtuins (SIRT1-7) regulate key biological processes like genomic stability, inflammation, cellular senescence, and metabolic functions, increasingly linked to cancer. In particular, SIRT1 shows dual roles, functioning both as a tumor suppressor or an oncogene, contributing to cancer initiation, progression, and metastasis as well as chemotherapy resistance. Despite extensive research in the past decade, the exact role of SIRT1 in BC, especially in TNBC, remains controversial. Recent findings suggest that SIRT1 can be modulated not only through pharmacological approaches but also using natural extracts, offering potential alternative or complementary therapeutic strategies. Additionally, SIRT1 activity is regulated by a complex network of miRNAs, highlighting the need for further investigation. This review aims to summarize recent studies to identify key insights into the role of SIRT1 and explore it as a potential therapeutic target in BC.

Tau protein aggregates exhibit distinct conformations across tauopathies, but their disease-specific protein interactions remain poorly understood. Here, we demonstrate that disease-specific tau conformations determine unique protein interaction landscapes across Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Through comprehensive interactome profiling of misfolded tau aggregates from PBS- and sarkosyl-soluble fractions. We identified 493 high-confidence proteins with remarkable disease specificity—notably, no common interactors overlapping across all three tauopathies. Machine learning classification achieved compelling discrimination between diseases using as few as 4-6 proteins features, demonstrating robust molecular signatures underlying clinical heterogeneity. AD derived tau aggregates uniquely engaged cellular metabolism machinery, including key glycolytic enzymes and TCA cycle proteins, alongside glutamate/GABA neurotransmitter cycling components, with the astrocytic glutamate transporter SLC1A2 showing 27-fold enrichment over other tauopathies. In contrast, PSP tau displayed the most distinctive profile, with extensive protein depletion (52/57 significant proteins) and selective enrichment of proteasome components, particularly PSMB7 showing >3000-fold abundance. DLB tau is associated with neurogenesis modulators while depleting neuroinflammatory mediators. These interaction patterns were validated through proximity ligation assays and correlated with distinct post-translational modification profiles, with PSP tau exhibiting globally elevated ubiquitination, AD showing mixed modification patterns, and DLB displaying minimal ubiquitination. Critically, sarkosyl-soluble fractions revealed reduced interactome complexity across diseases, except for PSP tau which maintained robust interactions with GPCR-ERK signaling and kinetochore proteins, suggesting unique aggregation mechanisms. Our findings establish that conformationally distinct tau strains dictate disease-specific protein interaction networks, providing molecular insight into tauopathy diversity and identifying novel therapeutic targets for precision medicine approaches in neurodegeneration.

RNA binding proteins (RBPs) containing intrinsically disordered regions (IDRs) are present in diverse molecular complexes where they function as dynamic regulators. Their characteristics promote liquid-liquid phase separation (LLPS) and the formation of membraneless organelles such as stress granules and nucleoli. IDR-RBPs are particularly relevant in the nervous system and their dysfunction is associated with neurodegenerative diseases and brain tumor development. Serpine1 mRNA-binding protein 1 (SERBP1) is a unique member of this group, being mostly disordered and lacking canonical RNA-binding domains. We defined SERBP1’s interactome, uncovered novel roles in splicing, cell division and ribosomal biogenesis, and showed its participation in pathological stress granules and Tau aggregates in Alzheimer’s brains. SERBP1 preferentially interacts with other G-quadruplex (G4) binders, implicated in different stages of gene expression, suggesting that G4 binding is a critical component of SERBP1 function in different settings. Similarly, we identified important associations between SERBP1 and PARP1/polyADP-ribosylation (PARylation). SERBP1 interacts with PARP1 and its associated factors and influences PARylation. Moreover, protein complexes in which SERBP1 participates contain mostly PARylated proteins and PAR binders. Based on these results, we propose a feedback regulatory model in which SERBP1 influences PARP1 function and PARylation, while PARylation modulates SERBP1 functions and participation in regulatory complexes.

Aggregation of microtubule-associated tau protein is a distinct hallmark of several neurodegenerative disorders such as Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). Tau oligomers are suggested to be the primary neurotoxic species that initiate aggregation and propagate prion-like structures. Furthermore, different diseases are shown to have distinct structural characteristics of aggregated tau, denoted as polymorphs. Here, we investigate the structural and functional differences of amplified brain-derived tau oligomers (aBDTOs) from AD, DLB, and PSP. Our results indicate that the aBDTOs possess different structural and morphological features that impact neuronal function, gene regulation, and ultimately disease progression. The distinct tau oligomeric polymorphs may thus contribute to the development of clinical phenotypes and shape the progression of diseases. Our results can provide insight into developing personalized therapy to target a specific neurotoxic tau polymorph.

Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer’s disease (AD). These aggregates are prevalent within intracellular compartments. Current tau immunotherapies have shown limited efficacy in clearing intracellular tau aggregates and improving cognition in clinical trials. In this study, we developed toxic tau conformation–specific monoclonal antibody-2 (TTCM2), which selectively recognized pathological tau aggregates in brain tissues from patients with AD, dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). TTCM2 potently inhibited tau-seeding activity, an essential mechanism underlying tauopathy progression. To effectively target intracellular tau aggregates and ensure rapid delivery to the brain, TTCM2 was loaded in micelles (TTCM2-ms) and administered through the intranasal route. We found that intranasally administered TTCM2-ms efficiently entered the brain in hTau-tauopathy mice, targeting pathological tau in intracellular compartments. Moreover, a single intranasal dose of TTCM2-ms effectively cleared pathological tau, elevated synaptic proteins, and improved cognitive functions in aged tauopathy mice. Mechanistic studies revealed that TTCM2-ms cleared intracellular, synaptic, and seed-competent tau aggregates through tripartite motif-containing 21 (TRIM21), an intracellular antibody receptor and E3 ubiquitin ligase known to facilitate proteasomal degradation of cytosolic antibody-bound proteins. TRIM21 was found to be essential for TTCM2-ms–mediated clearance of tau pathology. Our study collectively provides evidence of the effectiveness of nasal tau immunotherapy in targeting and clearing intracellular tau pathology through TRIM21 and enhancing cognition in aged tauopathy mice. This study could be valuable in designing effective tau immunotherapies for AD and other tauopathies.