Cerebral A beta deposition precedes reduced cerebrospinal fluid and serum A beta 42/A beta 40 ratios in the App(NL-F/NL-F) knock-in mouse model of Alzheimer's disease

• BackgroundA beta 42/A beta 40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer's disease (AD), but their temporal and correlative relationship with cerebral A beta pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD.MethodsCSF, serum, and brain tissue were collected from 3- to 18-month-old App(NL-F/NL-F) knock-in mice (n = 48) and 2-18-month-old App(NL/NL) knock-in mice (n = 35). The concentrations of A beta 42 and A beta 40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral A beta plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of A beta 42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay.ResultsIn App(NL-F/NL-F) knock-in mice, A beta 42/A beta 40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral A beta pathology, in which a more widespread A beta plaque burden and increased levels of A beta 42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, A beta 42/A beta 40 ratios in CSF and serum showed a negative hyperbolic association with cerebral A beta plaque burden as well as the levels of both soluble and insoluble A beta 42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral A beta plaque pathology were found in App(NL/NL) knock-in mice during the observation time.ConclusionsOur findings suggest a temporal sequence of events in App(NL-F/NL-F) knock-in mice, in which initial deposition of A beta aggregates in the brain is followed by a decline of the A beta 42/A beta 40 ratio in CSF and serum once the cerebral A beta pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral A beta pathology when assessed in CSF compared with serum.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

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

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

Nyckelord

Alzheimer's disease

Biomarker

Cerebrospinal fluid

Blood

Beta-amyloid

central-nervous-system

amyloid-beta

csf a-beta-42/a-beta-40

biomarkers

pet

a-beta-40

kinetics

brain

blood

tau

Neurosciences & Neurology

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)