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Targeting the BDNF/TrkB pathway for the treatment of amyloid beta 1‐40‒induced neurodegeneration: Focus on ocular manifestations of Alzheimer’s disease
Author(s) -
Lazaldin Mohd Aizuddin Mohd,
Iezhitsa Igor,
Agarwal Renu,
Agarwal Puneet,
Bakar Nor Salmah,
Ismail Nafeeza Mohd
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.037073
Subject(s) - tropomyosin receptor kinase b , neuroprotection , retinal , retina , brain derived neurotrophic factor , neurodegeneration , amyloid beta , neurotrophic factors , optic nerve , medicine , retinal ganglion cell , pathology , endocrinology , ophthalmology , neuroscience , biology , disease , receptor
Background Amyloidosis‐related alterations, similar to those seen in the brain of patients with AD, occur in the retina of glaucoma patients. Decreasing level of brain‐derived neurotrophic factor (BDNF) is believed to be associated with neurotoxic effect of Aβ peptide. Hence, in this study we investigated (1) the effect of BDNF on retinal damage induced by Aβ1‐40 and (2) involvement of BDNF‐TrkB signalling in neuroprotection by BDNF against beta 1‐40‐induced retinal damage in Sprague Dawley rats. Method Rats were divided into 3 groups: group 1 received PBS via intravitreal injection, group 2 received intravitreal Aβ1‐40 (5 nmol) while group 3 received BDNF (1 µg) as co‐treatment with Aβ1‐40 via intravitreal injection. Fourteen days after injections, rats were euthanized and eyes were enucleated, fixed and processed for histopathological examination of retinal and optic nerve morphology using H&E and toluidine blue staining, while retinal cells apoptosis were detected using TUNEL assay immunostaining. Estimation of GSH, SOD, catalase and BDNF level in retina was done through ELISA method. Additionally, retinal target proteins (caspase‐3, TrkB and ERK) and their gene expression level were assessed by Western blot analysis and real‐time PCR, respectively. Result BDNF showed protective effect against Aβ1‐40‐induced retinal and optic nerve injury by preserving retinal and optic nerve morphology, lowering number of apoptotic cells, improving oxidative status and restoring BDNF level. Neuroprotective effect of BDNF correlated with number of survived retinal ganglion cells after Aβ1‐40 exposure. Assessment of visual function of rats using visual object recognition tests showed that BDNF improved difficulties for rats to recognise the visual cues after Aβ1‐40 exposure thus showing that visual function of rats was relatively preserved by treatment with BDNF. It was observed that treatment with BDNF abolishes Aβ1‐40‐induced increase in retinal expression of caspase‐3 and upregulates TrkB and ERK levels as it was shown by western blot analysis. BDNF also suppresses Aβ1‐40‐induced transcriptional activity of caspase‐3 and increases TrkB and ERK transcriptional activity in the regulation of apoptosis. Conclusion Treatment with BDNF prevents Aβ1‐40 induced retinal injury by inhibiting Aβ1‐40‐induced neuronal apoptosis via downregulation of caspase 3 and upregulation TrkB and ERK levels.