Tau Passive Immunotherapy in Mutant P301L Mice: Antibody Affinity versus Specificity

Abstract

The use of antibodies to treat neurodegenerative diseases has undergone rapid development in the past decade. To date, immunotherapeutic approaches to Alzheimer’s disease have mostly targeted amyloid beta as it is a secreted protein that can be found in plasma and CSF and is consequently accessible to circulating antibodies. Few recent publications have suggested the utility of treatment of tau pathology with monoclonal antibodies to tau. Our laboratory has begun a systematic study of different classes of tau monoclonal antibodies using mutant P301L mice. Three or seven months old mutant tau mice were inoculated weekly with tau monoclonal antibodies at a dose of 10 mg/Kg, until seven or ten months of age were reached respectively. Our data strongly support the notion that in P301L animals treated with MC1, a conformational monoclonal antibody specific for PHF-tau, the rate of development of tau pathology is effectively reduced, while injecting DA31, a high affinity tau sequence antibody, does not exert such benefit. MC1 appears superior to DA31 in overall effects, suggesting that specificity is more important than affinity in therapeutic applications. Unfortunately the survival rate of the P301L treated mice was not improved when immunizing either with MC1 or PHF1, a high affinity phospho-tau antibody previously reported to be efficacious in reducing pathological tau. These data demonstrate that passive immunotherapy in mutant tau models may be efficacious in reducing the development of tau pathology, but a great deal of work remains to be done to carefully select the tau epitopes to target.

Specific Targeting of Tau Oligomers in Htau Mice Prevents Cognitive Impairment and Tau Toxicity Following Injection with Brain-Derived Tau Oligomeric Seeds

“…While studies have traditionally focused on targeting A␤ to prevent and treat AD, more research is now being dedicated to tau. However, most of the studies conducted using tau passive immunotherapy have targeted phosphorylated tau species known to be present in the late stages of aggregation and have resulted in a decrease of NFTs [35][36][37]. While NFTs have historically been the main tau species of interest, more results are emerging to suggest that toxicity and neuronal loss exceeds and occurs prior to NFT accumulation [1][2][3][4][5][6], thereby implicating the importance of intermediate tau species in toxicity.…”

“…Therefore, in order to stop the initial toxicity and the spread of disease, tau oligomers may be the best target. Moreover, it was recently shown that antibodies confer beneficial effects by targeting tau found extracellularly, implying that antibodies do not need to enter cells in order to reduce the toxic effects of tau, but may instead target tau which may be involved in the propagation of pathology [37,51]. Additionally, studies of tau therapeutics for neurodegenerative disease have primarily used transgenic mouse models expressing mutant tau.…”

“…A few studies have been conducted using antibodies against tau, yielding cognitive benefits, however the target has mainly been phosphorylated tau, rather than tau oligomers which confer toxicity. Additionally, these immunizations saw a decrease in NFTs, which do not seem to be toxic and may even be neuroprotective [35][36][37]. Therefore, using passive immunotherapy to target only toxic, soluble, oligomeric tau species appears to be a promising strategy.…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…2), or by blocking neuronal uptake of the protein [143]. Passive immunization with antiphospho-tau antibodies reduce tau pathology and functional deficits [137,[144][145][146], and antibodies targeting tau oligomers have also shown promise in transgenic models [136,147], including a concomitant upstream reduction in Aβ pathology [148]. In this sense, there are 3 anti-tau antibodies currently being studied in phase I trials (Table 1).…”

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

“…42,43 Briefly, the brain was removed and divided at the midline so that just one half of brain was dissected for biochemical analysis. Forebrain and hindbrain were homogenized separately using an appropriate volume of homogenizing buffer, a solution of TBS, pH 7.4, containing 10 mM sodium fluoride, 1 mM sodium vanadate and 2 mM EGTA, plus a complete Mini protease inhibitor cocktail (Roche, Branford, CT, USA).…”