Latina 2021 Acta Neuropathol Commun
| Latina V, Giacovazzo G, Cordella F, Balzamino BO, Micera A, Varano M, Marchetti C, Malerba F, Florio R, Ercole BB, La Regina F, Atlante A, Coccurello R, Di Angelantonio S, Calissano P, Amadoro G (2021) 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. Acta Neuropathol Commun 9:38. |
Latina Valentina, Giacovazzo Giacomo, Cordella Federica, Balzamino Bijorn Omar, Micera Alessandra, Varano Monica, Marchetti Cristina, Malerba Francesca, Florio Rita, Ercole Bruno Bruni, La Regina Federico, Atlante Anna, Coccurello Roberto, Di Angelantonio Silvia, Calissano Pietro, Amadoro Giuseppina (2021) Acta Neuropathol Commun
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. • Keywords: Alzheimer’s Disease, Mouse model, Neurodegeneration, Retina, Tau, Β-amyloid • Bioblast editor: Reiswig R • O2k-Network Lab: IT Bari Atlante A
Labels: MiParea: Pharmacology;toxicology
Pathology: Alzheimer's
Organism: Mouse Tissue;cell: Nervous system Preparation: Permeabilized tissue, Homogenate Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase Regulation: ATP
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