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Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau-associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD-associated neurodegeneration. • P-tau217 correlates with brain atrophy and cognitive impairment in AD patients • Antibody against p-tau217 attenuates pathology and neuronal loss in tauopathic mice • P-tau217 antibody restores brain function and proteostasis in tauopathic mice • An antibody targeting total tau leads to motor deficits in tauopathic mice Zhang et al. demonstrate that passive immunotherapy targeting p-tau217 is an effective strategy for intervening in tau-associated pathology and neurodegeneration in a mouse model of tauopathy, with potentially little side effect. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aβ- and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Despite many failures in developing AD treatment during the past 20 years, significant advances have been achieved in passive immunotherapy of AD very recently. Here, we review characteristics, clinical trial data, and mechanisms of action for monoclonal antibodies (mAbs) targeting key players in AD pathogenesis, including amyloid-β (Aβ), tau and neuroinflammation modulators. We emphasized the efficacy of lecanemab and donanemab on cognition and amyloid clearance in AD patients in phase III clinical trials and discussed factors that may contribute to the efficacy and side effects of anti-Aβ mAbs. In addition, we provided important information on mAbs targeting tau or inflammatory regulators in clinical trials, and indicated that mAbs against the mid-region of tau or pathogenic tau have therapeutic potential for AD. In conclusion, passive immunotherapy targeting key players in AD pathogenesis offers a promising strategy for effective AD treatment. ● Passive immunotherapy is a major strategy under clinical development for AD treatment. ● Monoclonal antibodies against Aβ including lecanemab and donanemab showed significant efficacy in phase III clinical trials. ● ARIA and brain atrophy cannot be ignored in Aβ-targeted immunotherapy. ● Passive immunotherapy targeting tau and neuroinflammation is at an early stage of development. [ABSTRACT FROM AUTHOR]