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.
Highlights
Alzheimer’s Disease (AD) is the most common of the conformational neurodegenerative disorders characterized by the conversion of a normal biological protein into a b-sheet-rich pathological isoform
A recent study using oligomers derived from synthetic Ab peptides reported that a high affinity specific binding site for Ab oligomers is the cellular prion protein (PrPC) and that PrPC is a requirement for acute Ab oligomer suppression of synaptic plasticity in hippocampal slices [6,7]
Treatment and Behavioral Studies Cognitive ability was assessed by the number of errors in consuming all 8 rewards using the radial arm maze (Figure 1)
Summary
Alzheimer’s Disease (AD) is the most common of the conformational neurodegenerative disorders characterized by the conversion of a normal biological protein into a b-sheet-rich pathological isoform. A recent study using oligomers derived from synthetic Ab peptides reported that a high affinity specific binding site for Ab oligomers is the cellular prion protein (PrPC) and that PrPC is a requirement for acute Ab oligomer suppression of synaptic plasticity in hippocampal slices [6,7]. We sought to test the hypothesis that short term treatment using monoclonal 6D11 could reverse memory impairment in an established APP/PS1 Tg mouse model of AD [10].
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