Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an alzheimer's disease model mouse

Abstract

BackgroundAlzheimer's Disease (AD) is the most common of the conformational neurodegenerative disorders characterized by the conversion of a normal biological protein into a β-sheet-rich pathological isoform. In AD the normal soluble Aβ (sAβ) forms oligomers and fibrils which assemble into neuritic plaques. The most toxic form of Aβ is thought to be oligomeric. A recent study reveals the cellular prion protein, PrPC, to be a receptor for Aβ oligomers. Aβ oligomers suppress LTP signal in murine hippocampal slices but activity remains when pretreated with the PrP monoclonal anti-PrP antibody, 6D11. We hypothesized that targeting of PrPC to prevent Aβ oligomer-related cognitive deficits is a potentially novel therapeutic approach. APP/PS1 transgenic mice aged 8 months were intraperitoneally (i.p.) injected with 1 mg 6D11 for 5 days/week for 2 weeks. Two wild-type control groups were given either the same 6D11 injections or vehicle solution. Additional groups of APP/PS1 transgenic mice were given either i.p. injections of vehicle solution or the same dose of mouse IgG over the same period. The mice were then subjected to cognitive behavioral testing using a radial arm maze, over a period of 10 days. At the conclusion of behavioral testing, animals were sacrificed and brain tissue was analyzed biochemically or immunohistochemically for the levels of amyloid plaques, PrPC, synaptophysin, Aβ40/42 and Aβ oligomers.ResultsBehavioral testing showed a marked decrease in errors in 6D11 treated APP/PS1 Tg mice compared with the non-6D11 treated Tg groups (p < 0.0001). 6D11 treated APP/PS1 Tg mice behaved the same as wild-type controls indicating a recovery in cognitive learning, even after this short term 6D11 treatment. Brain tissue analysis from both treated and vehicle treated APP/PS1 groups indicate no significant differences in amyloid plaque burden, Aβ40/42, PrPC or Aβ oligomer levels. 6D11 treated APP/PS1 Tg mice had significantly greater synaptophysin immunoreactivity in the dentate gyrus molecular layer of the hippocampus compared to vehicle treated APP/PS1 Tg mice (p < 0.05).ConclusionsEven short term treatment with monoclonal antibodies such as 6D11 or other compounds which block the binding of Aβ oligomers to PrPC can be used to treat cognitive deficits in aged AD transgenic mice.

CSF prion protein concentration and cognition in patients with Alzheimer disease

“…20 In animal experiments it was possible to counteract detrimental effects of Aβ and rescue parts of cognitive function by applying antibodies directed against PrP C . 19,[21][22][23] Considering all these findings, it stands to reason that further research on this topic is necessary, since PrP C might be useful as an AD biomarker as well as a potential therapeutic target. 24 Put into a clinical perspective, Meyne et al were able to demonstrate levels of CSF PrP C to be decreased in various neurodegenerative diseases including AD.…”

Cellular prion protein: A co-receptor mediating neuronal cofilin-actin rod formation induced by β-amyloid and proinflammatory cytokines

“…7 Treatment of aged APP swe / PS1DE9 mice with anti-PrP C antibodies allows a recovery of synaptic markers in the dentate gyrus of the hippocampus, a brain region associated with learning and memory. 18 Neuroinflammation occurs in TBI and many other neurodegenerative disorders. Proinflammatory cytokines, including tumor necrosis factor a (TNFa) and interleukin (IL)-1b, are increased in mild TBI and modulate deficits in motor coordination.…”

Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models

“…Interaction between A␤o and PrP C is essential for development of an array of AD features, including activation of certain signaling cascades, synaptotoxicity, inhibition of long term potentiation, memory impairment, and decreased survival in mice (25,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). However, it was also observed that A␤o can induce AD-like phenotypes independently of PrP C in J20 mice (44) and in some in vitro studies (23,24,45).…”