A sequential deposition of amyloid beta oligomers, plaques and phosphorylated tau occurs throughout life in the canine retina

Abstract

Aims: Cerebral amyloid burdens may be found in otherwise cognitively intact adults, often not showing worsening deficits with passing years. Alzheimer’s transgenic rodents have been widely used to investigate this phenomenon, but a spontaneous disorder in other animals, such as dogs that cohabit with humans and thus may have some shared environmental risks, may contribute and offer opportunities not possible in the smaller laboratory animals. In animals, the spontaneous disorder most comparable to Alzheimer’s disease (AD) affects mature to aged dogs and is designated canine cognitive dysfunction. Motivated by AD, many studies have revealed that amyloid progressively accumulates in the canine central nervous system, including the retina. Here, we investigated whether deposits of amyloid and/or tau can be found in the canine retina of neurologically normal animals from the first year of life to the elderly. Suppose canine ocular amyloid and tau are present from early life. In that case, that raises the question of whether similar patterns of accumulation occur in man, whether as part of aging, AD, or other. Methods: This study used eye tissues from 30 dogs with a variety of ophthalmic or other orbital disorders, of which 7/30 were 1-2 years old. Tissues were subdivided into dogs of three different age groups: young (1-5 years old), middle (6-10 years old), and old (≥ 11 years old). Results: Following immunostaining of tissue sections with nanobodies against retinal Aβ1-40 and Aβ1-42 oligomers, and antibodies against Aβ plaques (Aβp) and hyperphosphorylated Tau (p-Tau), our investigations revealed that accumulation of Aβ1-40 and Aβ1-42 oligomers were widespread in the retina in all age groups. In contrast, Aβp were detected in the middle and old age groups but not in the young age group. Furthermore, p-Tau staining was observed in four old dogs only, while other dogs were p-Tau free. Interestingly, both Aβo and Aβp co-localized in the middle and old age groups of dogs. Moreover, diffuse granular p-Tau co-localized with intracellular Aβo in the old age group. Finally, we also observed co-localization of Aβo and Aβp in the retinal vasculature which might be similar to cerebral amyloid angiopathy associated with AD. Conclusion: As far as we know, the presence of amyloid and tau in the canine retina is hitherto unreported. If similar, early-in-life subclinical retinal deposits occur in a human cohort perhaps identified by AD genetic risk factors, following this group may offer the prospect of preclinical therapeutic intervention in imminent dementia, a strategy recognized as likely necessary to impact this burgeoning disorder.