Distribution of Amyloid Precursor Protein and Amyloid-β Immunoreactivity in DBA/2J Glaucomatous Mouse Retinas

Goldblum, David; Kipfer-Kauer, Anna; Sarra, Gian-Marco; Wolf, Sebastian; Frueh, Béatrice E.

doi:10.1167/iovs.06-1249

Cited by 67 publications

(40 citation statements)

References 39 publications

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“…19,28 Accumulation of amyloid precursor protein and amyloid-b in the optic nerve is seen in mouse models of glaucoma. 29,30 We found paravascular CSF entry into the optic nerve up to and including the glia lamina, the mouse equivalent of the human lamina cribrosa. Entry of CSF tracers into the optic nerve head was not observed in our study.…”

Section: Discussionmentioning

confidence: 89%

Evidence for Cerebrospinal Fluid Entry Into the Optic Nerve via a Glymphatic Pathway

Mathieu

Gupta

Ahari

et al. 2017

Invest. Ophthalmol. Vis. Sci.

119

111

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PURPOSE. The purpose of this study was to determine whether cerebrospinal fluid (CSF) enters the optic nerve via a glymphatic pathway and whether this entry is size-dependent.METHODS. Fluorescent dextran tracers (fluorescein isothiocyanate [FITC]) of four different sizes (10, 40, 70, and 500 kDa) and FITC-ovalbumin (45 kDa) were injected into the CSF of 15 adult mice. Tracer distribution in the orbital optic nerve at 1 hour after injection was assessed in tissue sections with confocal microscopy. Tracer distribution within the optic nerve was studied in relation to blood vessels and astrocytes identified by isolectin histochemistry and glial fibrillary acidic protein (GFAP) immunofluorescence, respectively. Aquaporin 4 (AQP4) immunostaining was performed to assess astrocytic endfeet in relation to CSF tracer. RESULTS.One hour following tracer injection into CSF, all tracer sizes (10-500 kDa) were noted in the subarachnoid space surrounding the orbital optic nerve. In all cases, 10 kDa (n ¼ 4/4) and 40 kDa (n ¼ 3/3) tracers were noted within the optic nerve, while 70-kDa tracer was occasionally noted (n ¼ 1/4). Tracer found within the nerve was specifically localized between isolectin-labeled blood vessels and GFAP-positive astrocytes or AQP4-labeled astrocytic endfeet. The 500-kDa tracer was not detected within the optic nerve.CONCLUSIONS. To our knowledge, this is the first evidence of a glymphatic pathway in the optic nerve. CSF enters the optic nerve via spaces surrounding blood vessels, bordered by astrocytic endfeet. CSF entry into paravascular spaces of the optic nerve is size-dependent, and this pathway may be highly relevant to optic nerve diseases, including glaucoma.

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Section: Discussionmentioning

confidence: 89%

Evidence for Cerebrospinal Fluid Entry Into the Optic Nerve via a Glymphatic Pathway

Mathieu

Gupta

Ahari

et al. 2017

Invest. Ophthalmol. Vis. Sci.

119

111

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“…Strong APP and Ab immunoreactivity especially close to the lamina cribrosa, GCL and ON has been detected and higher levels of Ab40 are observed in the ON of old DBA/2 J mice [41]. Intra-vitreal administration of Ab42 and Ab25-35 peptides induced GC death and retinal degeneration in animal models [39].…”

Section: Glaucomamentioning

confidence: 96%

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

Gupta

Chitranshi

et al. 2016

Cell. Mol. Life Sci.

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Accumulation of amyloid β (Aβ) and its aggregates in the ageing central nervous system is regarded synonymous to Alzheimer's disease (AD) pathology. Despite unquestionable advances in mechanistic and diagnostic aspects of the disease understanding, the primary cause of Aβ accumulation as well as its in vivo roles remains elusive; nonetheless, the majority of the efforts to address pathological mechanisms for therapeutic development are focused towards moderating Aβ accumulation in the brain. More recently, Aβ deposition has been identified in the eye and is linked with distinct age-related diseases including age-related macular degeneration, glaucoma as well as AD. Awareness of the Aβ accumulation in these markedly different degenerative disorders has led to an increasing body of work exploring overlapping mechanisms, a prospective biomarker role for Aβ and the potential to use retina as a model for brain related neurodegenerative disorders. Here, we present an integrated view of current understanding of the retinal Aβ deposition discussing the accumulation mechanisms, anticipated impacts and outlining ameliorative approaches that can be extrapolated to the retina for potential therapeutic benefits. Further longitudinal investigations in humans and animal models will determine retinal Aβ association as a potential pathognomonic, diagnostic or prognostic biomarker.

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“…For age-related macula degeneration, Aβ is presumed to be involved in inflammation and neovascularisation [13]. Studies on the DBA/2J mouse model of glaucoma showed that sustained intraocular pressure (IOP) leads to extracellular Aβ accumulation in optic nerve heads and ganglion cell loss [16].…”

Section: Introductionmentioning

confidence: 99%

Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer’s disease

Dutescu

Crowston

et al. 2009

Graefes Arch Clin Exp Ophthalmol

128

141

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Distribution of Amyloid Precursor Protein and Amyloid-β Immunoreactivity in DBA/2J Glaucomatous Mouse Retinas

Abstract: Disruption of the homeostatic properties of secreted APP with consecutive Abeta cytotoxicity might be a contributing factor of ganglion cell loss in glaucomatous mouse retinas.

Cited by 67 publications

References 39 publications

Evidence for Cerebrospinal Fluid Entry Into the Optic Nerve via a Glymphatic Pathway

Evidence for Cerebrospinal Fluid Entry Into the Optic Nerve via a Glymphatic Pathway

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer’s disease

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