Systemic delivery of a specific antibody targeting the pathological N-terminal truncated tau peptide reduces retinal degeneration in a mouse model of Alzheimer’s Disease

Abstract

Retina and optic nerve are sites of extra-cerebral manifestations of Alzheimer’s Disease (AD). Amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau protein are detected in eyes from AD patients and transgenic animals in correlation with inflammation, reduction of synapses, visual deficits, loss of retinal cells and nerve fiber. However, neither the pathological relevance of other post-translational tau modifications—such as truncation with generation of toxic fragments—nor the potential neuroprotective action induced by their in vivo clearance have been investigated in the context of AD retinal degeneration. We have recently developed a monoclonal tau antibody (12A12mAb) which selectively targets the neurotoxic 20–22 kDa NH2-derived peptide generated from pathological truncation at the N-terminal domain of tau without cross-reacting with its full-length normal protein. Previous studies have shown that 12A12mAb, when intravenously (i.v.)-injected into 6-month-old Tg2576 animals, markedly improves their AD-like, behavioural and neuropathological syndrome. By taking advantage of this well-established tau-directed immunization regimen, we found that 12A12mAb administration also exerts a beneficial action on biochemical, morphological and metabolic parameters (i.e. APP/Aβ processing, tau hyperphosphorylation, neuroinflammation, synaptic proteins, microtubule stability, mitochondria-based energy production, neuronal death) associated with ocular injury in the AD phenotype. These findings prospect translational implications in the AD field by: (1) showing for the first time that cleavage of tau takes part in several pathological changes occurring in vivo in affected retinas and vitreous bodies and that its deleterious effects are successfully antagonized by administration of the specific 12A12mAb; (2) shedding further insights on the tight connections between neurosensory retina and brain, in particular following tau-based immunotherapy. In our view, the parallel response we detected in this preclinical animal model, both in the eye and in the hippocampus, following i.v. 12A12mAb injection opens novel diagnostic and therapeutic avenues for the clinical management of cerebral and extracerebral AD signs in human beings.

Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

“…Interestingly, we found that the most relevant AD-like cognitive, neurochemical and anatomopathological abnormalities classically detected in ICV-STZ mice under our experimental conditions were significantly improved by neutralization of the endogenously generated NH2htau following its removal via 12A12mAb administration. These findings provide new insights into the pivotal role of N-terminal tau cleavage in AD pathogenesis and indicate that it is in vivo targeted inhibition can be a novel therapeutic agent for the treatment of both familial [1,39] and sporadic forms of AD. The dose of 12A12mAb administered to mice in this study was calculated according to [1,39] and administered by intravenous injection into the lateral caudal vein on two alternated days up to 3 weeks.…”

“…These findings provide new insights into the pivotal role of N-terminal tau cleavage in AD pathogenesis and indicate that it is in vivo targeted inhibition can be a novel therapeutic agent for the treatment of both familial [1,39] and sporadic forms of AD. The dose of 12A12mAb administered to mice in this study was calculated according to [1,39] and administered by intravenous injection into the lateral caudal vein on two alternated days up to 3 weeks. The dose of 12A12mAb administered to mice in this study was calculated according to [1,39] and administered by intravenous injection into the lateral caudal vein on two alternated days up to 3 weeks.…”

“…In this context, we have recently demonstrated that: (i) the neurotoxic 20-22 kDa peptide deriving from the pathological truncation of tau at its N-terminal domain (aka NH 2 htau) accumulates into hippocampi from two well-established transgenic lines of fAD animal models, such as Tg2576 and 3xTg mice; (ii) its neutralization, following intravenous (i.v.) injection of the cleavage-specific anti-tau 12A12mAb, improves several relevant neuropathological and behavioral hallmarks of symptomatic (6-month-old) animals [1]; (iii) pathological N-truncation also participates in retinas and vitreous body deterioration associated with AD phenotype of Tg2576 mice and its deleterious effects are successfully antagonized by 12A12mAb immunization [39].…”

“…models, such as Tg2576 and 3xTg mice; (ii) its neutralization, following intravenous (i.v.) injection of the cleavage-specific anti-tau 12A12mAb, improves several relevant neuropathological and behavioral hallmarks of symptomatic (6-month-old) animals [1]; (iii) pathological N-truncation also participates in retinas and vitreous body deterioration associated with AD phenotype of Tg2576 mice and its deleterious effects are successfully antagonized by 12A12mAb immunization [39].…”

“…To address this purpose, we surgically infused the STZ in 6-month-old male C57BL/6J mice, which was given bilaterally into cerebral ventricles in single bolus (3 mg/Kg in 3 μL/side) alone or with 12A12mAb. This antibody was systemically delivered into lateral caudal vein on alternate days up to three weeks, as previously reported [1,39]. Animals were tested for their cognitive performance after 14 (short-term immunization regimen) and 21 (long-term immunization regimen) days [12,40].…”