Alzheimer’s disease (AD) is pathologically seen as a accumulation of β-amyloid (Aβ) protein Rabbit Polyclonal to NMBR. deposits and/or neurofibrillary tangles in association with progressive cognitive deficits. Aβ vaccinations reduced retinal Aβ deposits there was a marked increase in retinal microvascular Aβ deposition as well as local neuroinflammation manifested by microglial infiltration and astrogliosis linked with disruption of the retinal organization. These results provide evidence to support further investigation of the use of retinal imaging to diagnose AD and to MK-8745 monitor disease activity. Cerebral abnormalities including neuronal loss neurofibrillary tangles senile plaques with aggregated β-amyloid protein (Aβ) deposits microvascular deposition of Aβ and inflammation are well-known pathological hallmarks of Alzheimer’s disease (AD).1 2 3 Despite the controversial evidence about the contribution of Aβ to the development of AD-related cognitive deficits accumulation of toxic aggregated forms of Aβ plays a crucial role in the pathogenesis of familial types of AD.4 5 Overexpression of amyloid MK-8745 precursor protein (APP) in trisomy 21 altered APP processing resulting from mutations in APP presenilin 1 (PS1) or 2 (PS2) and as-of-yet unidentified other familial AD related mutations lead to Aβ deposition and Aβ plaques in the brain as well as cognitive abnormalities.6 7 Therefore to understand the molecular basis of amyloid protein deposition and to detect Aβ plaques in brain parenchyma ante-mortem are currently among the most active areas of research in AD. Besides cognitive abnormalities patients with AD commonly complain of visual anomalies in particular related to color vision 8 9 spatial contrast sensitivity 10 backward masking 11 visual fields 12 and other visual performance tasks.13 14 15 16 In addition to the damage and malfunction in the central visual pathways retinal abnormalities such as for example ganglion cell degeneration 17 decreased thickness from the retinal nerve dietary fiber coating 18 19 and optic nerve degeneration20 21 might in part take into account AD-related visual dysfunction. Although intracellular Aβ deposition continues to be recognized in both ganglion and zoom lens dietary fiber cells of individuals with glaucoma Advertisement or Down’s symptoms 22 23 24 25 additional typical hallmarks of AD have not yet been demonstrated. Interestingly thioflavine-S-positive Aβ plaques were recently found in the retinal strata of APPswe/PS1ΔE9 transgenic mice26 but not in the other animal models of AD. The current MK-8745 study used Tg2576 mice that constitutively overexpress APPswe and develop robust Aβ deposits in brain as well as cognitive abnormalities with aging.27 We assessed the pathological changes in the retina of aged mice following different immunization schemes. We immunized Tg2576 with fibrillar Aβ42 and with a prefibrillar oligomer mimetic that gives rise to a prefibrillar oligomer-specific immune response. Both types of immunogens have been shown to be equally effective in reducing plaque MK-8745 deposition and inflammation in Tg2576 mouse brains.28 In this study we also used another prefibrillar oligomer mimetic antigen that uses the islet amyloid polypeptide (IAPP) instead of Aβ but which gives rise to the same generic prefibrillar oligomer-specific immune response that also recognizes Aβ prefibrillar oligomers.29 Aβ plaques and microvascular Aβ deposition were observed in the control Tg2576 mouse retinas. In contrast Aβ and IAPP prefibrillar oligomer vaccinations differentially removed retinal Aβ deposits but exacerbated retinal amyloid angiopathy and inflammation as demonstrated by a significantly enhanced microglial infiltration and astrogliosis. Materials MK-8745 and Methods Preparation of Peptides The Aβ oligomer antigen was prepared from Aβ1-40 based on our previously published work.30 Briefly lyophilized Aβ1-40 peptides were resuspended in 50% acetonitrile in water and relyophilized. Soluble prefibrillar oligomers were prepared by dissolving 1.0 mg of peptide in 400 μl of hexafluoroisopropanol for 10～20 minutes at room temperature. The resultant seedless solution (100 μl) was added to 900 μl of MilliQ H2O in a siliconized Eppendorf tube. After 10～20 minutes incubation at room temperature the.