A pathological hallmark of Alzheimer’s disease (AD) is an accumulation of insoluble plaque containing the amyloid-β peptide (Aβ) of 40–42 aa residues1. Prefibrillar, soluble oligomers of Aβ have been recognized to be early and key intermediates in AD-related synaptic dysfunction2–9. At nanomolar concentrations, soluble Aβ-oligomers block hippocampal long-term potentiation7, cause dendritic spine retraction from pyramidal cells5,8 and impair rodent spatial memory2. Soluble Aβ-oligomers have been prepared from chemical syntheses, from transfected cell culture supernatants, from transgenic mouse brain and from human AD brain2,4,7,9. Together, these data imply a high affinity cell surface receptor for soluble Aβ-oligomers on neurons, one that is central to the pathophysiological process in AD. Here, we identify the cellular Prion Protein (PrPC) as an Aβ-oligomer receptor by expression cloning. Aβ-oligomers bind with nanomolar affinity to PrPC, but the interaction does not require the infectious PrPSc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the Aβ-oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent Aβ-oligomer binding to PrPC and rescue synaptic plasticity in hippocampal slices from oligomeric β. Thus, PrPC is a mediator of Aβoligomer induced synaptic dysfunction, and PrPC-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.

Soluble oligomers of the amyloid-β (Aβ) peptide are thought to play a key role in the pathophysiology of Alzheimer’s disease (AD). Recently, we reported that synthetic Aβ oligomers bind to cellular prion protein (PrPC) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Aβ peptide. We hypothesized that PrPC is essential for the ability of brain-derived Aβ to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1ΔE9 into Prnp−/− mice to examine the necessity of PrPC for AD-related phenotypes. Neither APP expression nor Aβ level is altered by PrPC absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrPC expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1ΔE9 transgenic mice. The AD transgenic mice with intact PrPC expression exhibit deficits in spatial learning and memory. Mice lacking PrPC, but containing Aβ plaque derived from APPswe/PSen1ΔE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrPC expression dissociates Aβ accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrPC.

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The production and aggregation of cerebral amyloid-␤ (A␤) peptide are thought to play a causal role in Alzheimer's disease (AD). Previously, we found that the Nogo-66 receptor (NgR) interacts physically with both A␤ and the amyloid precursor protein (APP). The inverse correlation of A␤ levels with NgR levels within the brain may reflect regulation of A␤ production and/or A␤ clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated A␤ clearance in APPswe/PSEN-1⌬E9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15-28 aa of A␤ associate with specific surface-accessible patches on the leucine-rich repeat concave side of the solenoid structure of NgR. In transgenic mice, subcutaneous NgR(310)ecto-Fc treatment reduces brain A␤ plaque load while increasing the relative levels of serum A␤. These changes in A␤ are correlated with improved spatial memory in the radial arm water maze. The benefits of peripheral NgR administration are evident when therapy is initiated after disease onset. Thus, the peripheral association of NgR(310)ecto-Fc with central A␤ residues provides an effective therapeutic approach for AD.

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Functional recovery is markedly restricted following traumatic brain injury (TBI), partly due to myelin-associated inhibitors including Nogo-A, myelin-associated glycoprotein ( MAG) and oligodendrocyte myelin glycoprotein (OMgp), that all bind to the Nogo-66 receptor-1 (NgR1). In previous studies, pharmacological neutralization of both Nogo-A and MAG improved outcome following TBI in the rat, and neutralization of NgR1 improved outcome following spinal cord injury and stroke in rodent models. However, the behavioral and histological effects of NgR1 inhibition have not previously been evaluated in TBI. We hypothesized that NgR1 negatively influences behavioral recovery following TBI, and evaluated NgR1 À/À mice (NgR1 À/À study) and, in a separate study, soluble NgR1 infused intracerebroventricularly immediately post-injury to neutralize NgR1 (sNgR1 study) following TBI in mice using a controlled cortical impact (CCI) injury model. In both studies, motor function, TBI-induced loss of tissue, and hippocampal b-amyloid immunohistochemistry were not altered up to 5 weeks post-injury. Surprisingly, cognitive function (as evaluated with the Morris water maze at 4 weeks post-injury) was significantly impaired both in NgR1 À/À mice and in mice treated with soluble NgR1. In the sNgR1 study, we evaluated hippocampal mossy fiber sprouting using the Timm stain and found it to be increased at 5 weeks following TBI. Neutralization of NgR1 significantly increased mossy fiber sprouting in sham-injured animals, but not in brain-injured animals. Our data suggest a complex role for myelin-associated inhibitors in the behavioral recovery process following TBI, and urge caution when inhibiting NgR1 in the early post-injury period.

Study Design: Narrative review. Objectives: To discuss the relationship between degenerative cervical myelopathy (DCM) and vitamin B 12 deficiency. Specifically, it is the aim to outline the rational for future research into assessment and therapeutic optimization of vitamin B 12 in the treatment of DCM.Methods: Literature review. Results: DCM is the commonest cause of spinal cord impairment, with an average age of presentation in the sixth decade. Patients at this age have also been reported to have a high prevalence of vitamin B 12 deficiency, with estimates of up to 20% in the elderly. Vitamin B 12 deficiency can result in subacute combined degeneration of the spinal cord (SACD), and several case reports have pointed to patients with both DCM and SACD. Both SACD and reversible compressive injury due to DCM necessitate remyelination in the spinal cord, a process that requires adequate vitamin B 12 levels. Basic science research on nerve crush injuries have shown that vitamin B 12 levels are altered after nerve injury and that vitamin B 12 along with dexamethasone or nonsteroidal anti-inflammatory drugs can reduce Wallerian degeneration. Furthermore, it has been suggested that a combination of B-vitamins can reduce glutamate-induced neurotoxicity.Conclusions: Given the high prevalence of clinical and subclinical vitamin B 12 deficiency in the elderly, the role of vitamin B 12 in myelination, and vitamin B 12 deficiency as a differential diagnosis of DCM, it is important to investigate what role vitamin B 12 levels play in patients with DCM in terms of baseline neurological function and whether optimization of vitamin B 12 levels can improve surgical outcome. Furthermore, the routine assessment of vitamin B 12 levels in patients considered for DCM surgery should be considered.