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Investigating amyloid and tau protein pathology in the retina in healthy and neurodegenerative disease conditions
Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to progressive neuro athological and cognitive deficits in the CNS. The early neuropathological changes that occur in the brain are critical to understand the disease mechanisms. Glaucoma is another neurodegenerative disorder that affects the retina and causes irreversible vision loss by damaging retinal ganglion cells (RGCs) and o tic nerve. The disease characterised by increased intraocular pressure (IO ) in most patients. The retina is integral art of the CNS and can serve as a window to study the shared neuro pathological mechanisms in various neurodegenerative conditions. Several studies have shown significantly elevated levels of Amyloid and tau proteins in the retina in AD and glaucoma conditions. It is not clear whether the increased levels of these AD associated archetypal proteins is a cause or result of the disease pathology. This study has aimed to understand the early retinal changes in AD and determining the effects of amyloid β and tau protein on the retinal neurons in healthy and experimental glaucoma conditions. Our mass spectrometric (MS) data has revealed significant upregulation of amyloid precursor protein (APP) and APP associated proteolytic and proteasomal enzymes in the young APP / S1 mouse model of AD. The results also indicate both protein synthesis and elongation associated proteins significantly down regulated in the retina of the APP / PS1 mice. Further, parallel to the changes in the retina, we have also determined protein alterations occurring in four different regions of brain of APP / PS1 mice. According to the brain tissue analysis, hippocampus and the cortex regions of the brain indicate significant damage in early stages compared to the cerebellum region. Additionally, we investigated the effects of amyloid β exposure on the retinal neurons in culture and observed alterations in the cytoskeletal organisation and ribosomal and oxidative phosphorylation machinery. The effects of tau protein modulation on the retina were investigated in mice using AAV gene therapy. AAV9- mediated gene therapy to overexpress and knockdown tau resulted in significantly elevated tau expression and it’s silencing respectively in both retinal and brain tissues. Both conditions had a negative effect on function and inner retinal structure indicating that a normal tau protein expression is essential to maintain the inner retinal integrity. However, in glaucomatous retinas AAV mediated tau protein silencing was shown to provide relative protection against the inner retinal functional and structural degenerative changes. Together, the results demonstrate that both tau and amyloid protein modulation can alter the functional and structural attributes of the retina and suggested that silencing of Tau expression under experimental glaucoma conditions can provide some neuroprotection. The study confirms that Aβ and tau protein may be potential targets in AD and glaucoma neurodegeneration
