Neha Rao

 Introduction. Alzheimer’s Disease (AD) is a neurodegenerative disorder affecting 5.3 million people in the U.S. aged 65 and older, and is the most common cause of dementia¹. Changes in olfaction, hearing, and motor skill precede the onset of cognitive impairments and dementia². AD progression includes worsening memory loss and ultimate cognitive deterioration^2,3. Abnormal deposition of misprocessed and aggregated proteins is a common final pathway of most neurodegenerative diseases, including AD⁴. A key histopathological characteristic of AD is the presence of intracellular neurofibrillary tangles composed of hyper-phosphorylated tau protein. In AD, tau undergoes several other posttranslational modifications in addition to phosphorylation that contribute to the tau aggregation and disease pathology^4,5. Studies have shown that blocking phosphorylation and eliminating truncated tau in mouse models prevent further neurodegeneration. These findings suggest that tau is an attractive target for Alzheimer’s therapy. Methods. Two studies were conducted to discern the therapeutic effects of targeting tau. The first study utilized tau-targeting passive immunotherapy. Two different mouse models were used to test three specific antibodies: IgG control, anti-phospho-independent tau (termed pan-Tau Ab) and two anti-pS404 tau antibodies (termed pS404 mAb1 and pS404 mAb2) which were obtained from Neotope Biosciences. Blood and tissue samples from the mouse models were collected for Western Blotting and serology evaluation⁶. The second study explored cleavage of tau via asparagine endopeptidase (AEP) utilizing an in vitro cleavage assay with kidney lysates. Mass spectrometry was utilized to determine cleavage site and tau fragment size. To assess the physiological role of AEP, Lgmn−/− mice were bred with tau P301S transgenic mice to knock out AEP in tau P301S mice⁷. Results. After antibody treatment in the first study, tau aggregation was suppressed and the clearance of already formed tau aggregates within affected cortical neurons were enhanced in mice. Notably, K3 mice passively immunized with the tau-specific antibody pS404 mAb2 showed significantly reduced PHF1 phosphorylation in the cortex⁶. From the second study, deletion of AEP from tau P301S transgenic mice substantially reduces tau hyperphosphorylation, alleviates synapse loss and rescues impaired hippocampal synaptic function. Additionally, infection of uncleavable tau N255AN368A mutant rescues tau P301S-induced pathological and behavioral defects⁷. Conclusions. Developing passive immunotherapy for AD based on the specific antibody pS404 mAb2 could alleviate and/or halt the effects of tau pathology. Alternatively, blockade of AEP may provide an innovative therapeutic intervention for reducing abnormal tau deposition and hyperphosphorylation, thus protecting against memory loss and cognitive impairment.

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