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A pathological hallmark of Alzheimer's disease is an accumulation of insoluble plaque containing the amyloid-β peptide of 40-42 amino acid residues (1). Prefibrillar, soluble oligomers of amyloid-β have been recognized to be early and key intermediates in Alzheimer's-disease-related synaptic dysfunction (2-9). At nanomolar concentrations, soluble amyloid-β oligomers block hippocampal long-term potentiation (7), cause dendritec spine retraction from pyramidal cells (5,8) and impair rodent spatial memory (2). Soluble amyloid-β oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer's disease brain (2,4,7,9). Together, these data imply a high-affinity cell-surface receptor for soluble amyloid-β oligomers on neurons-one that is central to the pathophysiological process in Alzheimer's disease. Here we identify the cellular prion protein ([PrP.sup.C]) as an amyloid-β-oligomer receptor by expression cloning. Amyloid-β oligomers bind with nanomolar affinity to [PrP.sup.C], but the interaction does not require the infectious [PrP.sup.Sc] conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-β oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-β-oligomer binding to [PrP.sup.C] and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-β. Thus, [PrP.sup.C] is a mediator of amyloid-β-oligomer-induced synaptic dysfunction, and [PrP.sup.C]-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease., To characterize amyloid-β-oligomer-binding sites, we synthesized amyloid-β(1-42) peptide conjugated to biotin through the α amino group (biotin-Aβ42), and then denatured the peptide and allowed oligomers to form as described for [...]

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. [ABSTRACT FROM AUTHOR]

The production and aggregation of cerebral amyloid-β (Aβ) 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 Aβ and the amyloid precursor protein (APP). The inverse correlation of Aβ levels with NgR levels within the brain may reflect regulation of Aβ production and/or Aβ clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated Aβ clearance in APPswe/PSEN-1ΔE9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15-28 aa of Aβ 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 Aβ plaque load while increasing the relative levels of serum Aβ. These changes in Aβ 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 Aβ residues provides an effective therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Sciubba is a consultant for Medtronic, Depuy-Synthes, Stryker, Nuvasive, and K2M. The other authors have no conflicts of interest to declare.