CSF Aβ42 and Aβ40 and their relation to brain soluble and insoluble Aβ in the 5xFAD mouse model of Alzheimer's disease

• BACKGROUND: In patients with AD, CSF Aβ42 is reduced while Aβ40 remains unchanged. It has been suggested that altered CSF Aβ42 is due to aggregation of this peptide into insoluble plaques, resulting in less soluble Aβ42 available for secretion to the CSF. However, the relations between soluble and insoluble Aβ42 and Aβ40 in the brain and the concentrations of these Aβ peptides in CSF are not well studied. METHODS: CSF and cortical brain tissue was collected from 2, 4, 6, and 12 months old male and female 5xFAD mice (n=45). CSF Aβ42 and Aβ40 concentrations were measured using Single molecule array (Simoa) technology. Brain sections were prepared and immunohistochemically (IHC) stained using antibodies specific for Aβ42 and Aβ40. The concentrations of Aβ42 and Aβ40 in soluble (extracted with TBS) and insoluble (extracted with formic acid) cortical brain fractions were determined by the Meso Scale Discovery technique. RESULTS: CSF Aβ42 was decreased over time whereas CSF Aβ40 remained unaltered (Fig 1). In the same mice, IHC revealed an age-related increased deposition of both Aβ42 and Aβ40 in insoluble plaques from 2 months of age (Fig 2). Moreover, measurements of Aβ42 and Aβ40 in soluble and insoluble cortical brain fractions showed increased concentrations of both peptides over time (Fig 3). CSF Aβ42 correlated inversely with cortical deposition of Aβ42 determined with IHC and the concentrations of Aβ42 in soluble and insoluble brain fractions. In contrast, no such correlations were found for Aβ40 (Fig 4). Although cortical levels of the two Aβ peptides were higher in females than in males, these sex differences were not reflected in CSF (Fig 5). CONCLUSIONS: Although significant depositions of both Aβ42 and Aβ40 were found in the brain, only Aβ42 was altered in CSF. Together with the finding that Aβ42 was increased, and not reduced, in soluble cortical brain fractions, this may suggest that mechanisms other than aggregation of Aβ42 into insoluble plaques contribute to decreased CSF concentrations of this Aβ peptide in 5xFAD mice. However, additional characterization of Aβ in the soluble brain fraction is needed to further understand its relation to the concentrations in CSF.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Publication and Content Type

art (subject category)

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