Behind the Paper

Protein misfolding disturbs cell communications and brain function: the perpetrator tau

Nicolas G. Bazan Oct 03, 2025

Our paper (Ji et al., 2025) reflects one of the approaches that we are using to ascertain specific dysfunctions in a Tau model that recapitulates aspects of Alzheimer’s disease (AD). A goal in our laboratory is to identify neuroprotection mediators 1, particularly those involved in Tauopathies 2. Here, I highlight Tau pathology at the onset and progression of neurodegenerative diseases. Since our laboratory aims to contribute to uncovering neuroprotective therapies, I also discuss the protective mutations Christchurch R136S variant APOE3ch and the Reelin,  the potential of lipid mediators as a therapy for tauopathies, and other approaches being developed, including antibodies. 

The trigger, function, and trajectory of AD-related brain neuroinflammation contribute to the onset and progression of AD, aggravating both Aβ and tau pathologies. Inflammation, which includes inflammaging (a low-grade, chronic inflammatory condition), is a dynamic process that differs at the early and late stages of AD 3. Moreover, a shift in approaches to longevity, focusing on building resiliency for successful aging, is evolving 4.

 

Neurofibrillary tangles and tau seeds and aggregates, propagating misfolded toxic tau correlating with clinical severity and cognitive decline

Tau aggregates accumulate in neurons and dendrites in diseases referred to as taupathies. They include AD, Pick’s (PiD), Lewy bodies (DLB); progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD); and chronic traumatic encephalopathy (CTE), a neurodegeneration that evolves after repeated head trauma. Tau pathologies also occur in synucleinopathies, where co-occurrence of tau and α-synuclein (α-syn) aggregates accelerates tau seeding, implying that α-syn and tau seeding processes are interrelated and that multiple misfolded proteins are also engaged in neurodegenerative diseases.

Tau appears as 6 isoforms, with 0, 1, or 2 N-terminal inserts and 3 or 4 repeats (R) within the microtubule binding region. Tauopathies are characterized by the accumulation of 3R, 4R, or 3R/4R tau isoforms, with AD being characterized by 3R/4R tau filament accumulation. Pathological deposition of tau is initiated by the transition of monomeric tau, an intrinsically disordered protein, into misfolded conformations that form toxic tau aggregates 5–7.

To contain self-propagating misfolded toxic tau, anti-tau monoclonal antibodies seemed to halt tauopathy progression. However, since mAbs target extracellular tau, intracellular pathological tau aggregates remain unaffected. Despite this, clinical trials tested anti-­tau mAbs based on mouse studies, and trials with the mAbs tilavonemab and gosuranemab failed to exert improvements in patients with tauopathies 8. It is evolving that intraneuronal tau aggregates and synaptic tau seeds are more decisive in the disease than extracellular counterparts. Tau pathology propagates through exosomes or nanotubes, protecting tau seeds from therapeutic antibodies. Thus, to attenuate tauopathy progression and cognitive decline, developing immunotherapies that target intracellular tau and block seeding activity.

Additional challenges to anti-­tau mAbs include the fact that they should recognize pathological and toxic tau conformations rather than the abundant physiological tau. To solve some of these issues, a toxic tau conformation–specific mAb (TTCM2) that detected disease-­relevant tau aggregates in postmortem brain has been developed, including improved delivery to the brain upon intranasal delivery in tauopathy mice. The intranasal route is a viable, noninvasive, safe approach for effective drug delivery to the brain. In fact, this route is effective in delivering neuroprotective lipid mediators in experimental models of brain injury 9,10 and in rescuing memory and gamma oscillation impairments in an AD model 11.

 

The Christchurch R136S variant APOE3ch and the Reelin mutation diminished Aβ plaques and prominently reduced tau seeding and spreading

AD, the most frequent cause of dementia, presents as early-clinical onset and late-clinical onset (over age 65). Hallmarks comprise amyloid-β (Aβ) in plaques, intraneuronal aggregation of hyperphosphorylated tau in neurofibrillary tangles (NFTs), and neuroinflammation. In both instances, Aβ plaques start forming about 20 years before the onset of cognitive decline, which concurs with tau pathology.  1%–2% autosomal dominant AD is caused by mutations in APP, PSEN1, or PSEN2 that present as early-onset AD.

The APOE4 gene allele enhances AD risk, and the APOE2 allele diminishes AD risk. The first identified protective mutation against autosomal dominant AD is a homozygous variant in two APOE3 alleles—R136S—called APOE3-Christchurch (APOE3ch). The APOE3ch homozygous carrier with the PSEN1-E280A mutation developed mild cognitive decline in her 70s, which displayed limited tauopathy in the temporal and parietal cortex. A woman with the PSEN1 E280A mutation, who remained cognitively healthy into her 70s, 30 years after the expected age of AD onset associated with the PSEN1-E280A mutation,  had two copies of a protective genetic variation in the APOE gene, the Christchurch mutation (APOE3ch), which prevented the spread of abnormal tau proteins, despite amyloid plaques 12,13. 

A knock-in mouse expressing human APOE3-R136S, compared to APOE3 KI mice, showed that APOE3ch would affect early tau seeding and spreading induced by amyloid deposition 14. APOE3ch augmented microglial response around plaques and myeloid cell phagocytosis and degradation of human tau fibrils. Enhanced tau uptake by myeloid cells correlates with decreased binding of APOE3ch to receptors HSPG and LRP1. Thus, APOE3ch hinders amyloid-induced tau seeding and spreading via microglia 14.  A second protective mutation was reported in a man with the PSEN1 E280A mutation, who remained resilient to AD for decades,  linked to a rare mutation in the Reelin gene that fosters the disposal of misfolded tau proteins 15.

We are also studying the landscape of changes in lipid mediators and find that tau pathology has a more pronounced effect on bioactive lipid mediators than amyloid pathology, as represented in 10-month-old R955-hTau+/- rats 2. These observations reveal a complex balance between pro-inflammatory and pro-homeostatic events, which may help identify disease stages as well as differentiate AD from other tauopathies at stages preceding overt neuronal loss and, therefore, at stages more prone to intervention.

 

References

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  2. Do Carmo, S. et al. Differential effect of an evolving amyloid and tau pathology on brain phospholipids and bioactive lipid mediators in rat models of Alzheimer-like pathology. J Neuroinflammation 21, 185 (2024).
  3. Emre, C. et al. Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer’s disease. Acta Neuropathol Commun 9, 116 (2021).
  4. Bazan, N. G. Brain Aging and Resilience: Exploring the Adaptability of the Human Brain in the Face of Aging and Adverse Conditions. (Springer, 2025). doi:10.1007/978-3-031-94431-4.
  5. Shi, Y. et al. Structure-based classification of tauopathies. Nature 598, 359–363 (2021).
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  9. Reid, M. M. et al. Integrated inflammatory signaling landscape response after delivering Elovanoid free-fatty-acid precursors leading to experimental stroke neuroprotection. Scientific Reports 13, 15841 (2023).
  10. Bazan, N. G. et al. Elovanoids, a Novel Class of Lipid Mediators, Are Neuroprotective in a Traumatic Brain Injury Model in Rats. Biomedicines 12, 2555 (2024).
  11. Emre, C. et al. Intranasal delivery of pro-resolving lipid mediators rescues memory and gamma oscillation impairment in AppNL-G-F/NL-G-F mice. Commun Biol 5, 245 (2022).
  12. Nelson, M. R. et al. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci 26, 2104–2121 (2023).
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  14. Chen, Y. et al. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell 187, 428-445.e20 (2024).
  15. Lopera, F. et al. Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Nat Med 29, 1243–1252 (2023).