Soluble aggregates (oligomers) of amyloid β (amyloid beta; hereinafter, also referred to as “Aβ”) have been suggested as the primary pathogenic cause of Alzheimer's disease (hereinafter, also referred to as “AD”) (Non Patent Literature 1).
Although it is commonly recognized that the Aβ oligomer in the CSF represents an important clinical biomarker for measuring the medicinal effect of an agent targeting Aβ such as an anti-Aβ antibody, detailed attributes (such as structure, size, and origin) of the Aβ oligomer actually eliciting pathology in AD patients remain elusive (Non Patent Literature 2). Some way of measuring such pathological Aβ oligomers is thus desired.
A method that biochemically measures Aβ oligomer levels in human CSF, and a bioassay that measures the bioactivity of human CSF are currently available as methods for measuring Aβ oligomer in human CSF. Assay systems based on immunoassay have been studied as a method for biochemically measuring Aβ oligomer levels. However, because of the considerably low Aβ oligomer levels in CSF, there is hardly any report that had success in such measurement. The bioassay is available as an in vitro test and an in vivo test, as described below.
There is a report of an in vitro test in which cell death, synaptic degeneration, and other changes occurred in cultured nerve cells acted upon by a high concentration (nM order) of artificial Aβ oligomer (Non Patent Literature 3).
There are also reports that nerve cells are damaged when cell lines from nerve cells are acted upon by CSF collected from an AD patient (hereinafter, referred to as “AD patient CSF”) (Non Patent Literatures 4 and 5).
There is also a report that electrostimulation of a mouse hippocampus slice after exposure to an artificial Aβ oligomer suppresses long-term potentiation (hereinafter, “LTP”), which is a phenomenon associated with brain's memory formation, in the slice (Non Patent Literature 6).
As to the in vivo test, there is a report in which electrostimulation after administration of AD patient CSF in the rat cerebral ventricle suppressed LTP in the rat brain (Non Patent Literature 7).
There are also reports that the learning behavior of rats or mice is obstructed when an artificial Aβ oligomer or oligomers extracted from cultured cells or brain tissue are administered into the rat or mouse cerebral ventricles (Non Patent Literatures 8 and 9). However, there is no report of administering AD patient CSF to rodents, and measuring the animals for the presence or absence of any resulting learning behavior impairment.
While bioassays of Aβ oligomers in AD patient CSF are available as described above, there is no established bioassay that can quickly and efficiently evaluate human CSF bioactivity, namely human CSF toxicity, with small amounts of CSF.
USPTO Backgrounds
USPTO Backgrounds