Correlation between p-tau217 and Alzheimer’s Disease Neurodegeneration and the Ameliorative Effects of Targeting p-tau217 Immunotherapy in Mouse Tauopathy

Introduction

Neuron loss is a core issue in Alzheimer’s Disease (AD). However, to date, no therapy can halt the neurodegenerative changes associated with AD. Tau is a microtubule-associated protein, mainly expressed in neurons, that regulates microtubule polymerization and stability. In the central nervous system, abnormal tau aggregation is a pathological hallmark of various neurodegenerative disorders (tauopathies), including AD. Despite tau being considered crucial in AD-related neurodegeneration, the specific forms and mechanisms remain unclear.

Recently, a study by Zhang et al., published in Neuron, reported the development of a monoclonal antibody (mAb2a7) targeting the human tau protein at the phosphorylation site 217 (p-tau217). They observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Through passive immunotherapy in a ps19 tauopathy mouse model, the researchers found that mAb2a7 significantly reduced tau pathology and aggregation, improved neuron loss, and even restored brain function. This discovery provides a potential target for treating AD-related neurodegeneration.

Research Background

p-tau217 levels rise in cerebrospinal fluid and plasma during the early stages of AD and are more closely associated with tau deposition in the AD brain. Studies also show that different phosphorylated forms of tau change significantly at different stages of AD, but key inferences are not fully elucidated. Conversely, tau removal in mice leads to Parkinsonian symptoms and brain insulin resistance, indicating that tau’s physiological function is indispensable. Therefore, specifically targeting pathological or neurotoxic forms of tau might provide therapeutic options for tauopathies, with targeting highly phosphorylated forms of tau being a promising approach.

Research Methods

This study was conducted by Denghong Zhang, Wei Zhang, Chen Ming, and others, affiliated with the Xiamen University First Affiliated Hospital Brain Science Center, Tangdu Hospital Neurology Department, Macau University of Science and Technology Faculty of Health Sciences, Chongqing Medical University Brain Science and Disease Research Institute, Fujian Medical University Hospital, and other institutions. The paper was published in the 2024 issue of Neuron.

The researchers developed a monoclonal antibody mAb2a7 specifically targeting p-tau217. They validated its specificity and affinity for recognizing p-tau217 using immunofluorescence (IF) staining and immunoblotting (IB). They also evaluated the effects of passive immunotherapy using the ps19 tauopathy mouse model. Additionally, the study compared the effects of the mAb2a7 antibody and an anti-total tau antibody (13g4) on brain function and tau pathology.

Antibody Specificity and Affinity Verification

The researchers first generated a mouse monoclonal antibody targeting the phosphorylated tau217 (p-tau217) peptide and identified an IgG2b clone, mAb2a7. Surface plasmon resonance (SPR) analysis validated the high affinity of mAb2a7 for the p-tau217 peptide with minimal cross-reactivity. IB analysis further demonstrated that mAb2a7 could recognize human tau protein in ps19 tau transgenic mouse brains but not in wild-type mouse tau protein.

Passive Immunotherapy Methods

To test whether mAb2a7 could modulate neurodegeneration and tau pathology accumulation in ps19 mice, the researchers delivered mAb2a7 intranasally (IN) and intravenously (IV). The results showed that IN delivery was more efficient in delivering the antibody into the mouse brain, where it primarily bound to tau, whereas IV-delivered antibodies were mostly free-form. Single-dose mAb2a7 ELISA tests across different time points on brain and plasma samples further confirmed that the IN route is particularly suitable for immunotherapy of brain diseases.

Therapeutic Efficacy Evaluation

The study found that mAb2a7 treatment significantly reduced tau pathology and aggregation in ps19 mouse brains, reduced tau-associated neuronal apoptosis and brain atrophy, and restored normal cognitive and behavioral function. Specifically, multiple behavioral tests, like the open field test, rotarod test, and Morris water maze test, demonstrated that mAb2a7 could restore the cognitive and motor functions of infected mice.

Additionally, the study analyzed the antibody’s effects on restoring protein homeostasis in mice. Proteomics analysis showed that mAb2a7 treatment restored the expression of proteins involved in synaptic function and neural activity while downregulating proteins associated with oxidative stress and apoptosis. These results suggest that AD progression might be driven by protein homeostasis disruption caused by tau pathology accumulation, and mAb2a7 provides protective effects by restoring protein balance.

The study also compared the therapeutic effects of the anti-total tau antibody 13g4, finding that, although 13g4 could reduce tau pathology and neurodegeneration, it caused significant motor function impairments in mice, suggesting that selectively targeting tau forms may have fewer side effects.

Research Significance and Value

This study has significant scientific and clinical implications for AD treatment. Firstly, targeting specific phosphorylated forms of tau rather than total tau protein provides a more precise therapeutic approach and may reduce side effects caused by lowering total tau protein levels. Secondly, the research validates the efficacy and safety of targeted immunotherapy against highly phosphorylated tau in experimental animals, providing strong support for subsequent clinical trials.

The study also demonstrates that the intranasal route is an effective strategy for efficiently delivering antibodies into the brain, offering new approaches to treating brain diseases compared to traditional intravenous routes. This research showcases that precise and specific targeting strategies, combined with effective delivery methods, may provide solutions for treating neurodegenerative diseases like Alzheimer’s and improve patient quality of life.

The study not only provides a potential therapeutic target for AD-related neurodegeneration but also presents an effective brain disease-targeted immunotherapy strategy of considerable scientific and clinical value.