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.