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.
Highlights
Basic and translational researches have recently focused their attention on the eye as an initial site of extra-cerebral manifestations of Alzheimer’s Disease (AD), a neurodegenerative disorder which has been historically perceived as confined to the brain [1, 2]
Based on the similarities described between the visual system and the Central Nervous System (CNS) both in human and rodent experimental models of AD neurodegeneration, we investigated whether: (i) tau cleavage—in particular at its N-terminal extremity—could be detected in eyes of symptomatic Tg2576 mice, as we previously found in the hippocampus; (ii) the systemic delivery of 12A12mAb targeting the pathogenic 20–22 kDa N H2htau fragment could represent a valuable therapeutic opportunity to ameliorate the retinal injury, known to be associated with their phenotype [1, 6, 9, 72]
Filters were probed with three different tau antibodies reacting against different epitopes located around the extremity and middle N-terminal end of protein, including caspase-cleaved protein (CCP)-NH2 tau (26-36aa) [51, 64], BT2 (194-198aa) and DC39N1 (45-73aa). β-actin was used as loading control
Summary
Basic and translational researches have recently focused their attention on the eye as an initial site of extra-cerebral manifestations of Alzheimer’s Disease (AD), a neurodegenerative disorder which has been historically perceived as confined to the brain [1, 2]. Other signs of ocular degeneration—such as loss of retinal ganglion neurons, atrophy of nerve fiber layer, thinning of the macular ganglion cell complex, axonal degeneration in the optic nerve, alteration of blood flow rate—reflect, and even anticipate, the hallmarks of AD cerebral deterioration [1, 2, 13, 19]. 33% of individuals diagnosed with Mild Cognitive Impairment (MCI), a prodromal stage of AD, have substantial visual motion perception deficits and retinal layer thickness together with microvascular alterations [36, 38,39,40,41,42]. Advances in retinal imaging and evidence of a positive response to immunotherapy of AD animal models prospect widespread population screening, early diagnosis, monitoring before the disease manifests with irreversible clinical symptoms and, eventually, developing disease-modifying intervention [48]
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