Changes in Amyloid-β and Tau in the Cerebrospinal Fluid of Transgenic Mice Overexpressing Amyloid Precursor Protein

Changes in Aβ and Tau in the CSF of APP transgenic mice mirror the temporal sequence and magnitude of changes in these proteins in the CSF of Alzheimer’s disease patients. From Bedside Back to Bench The pathology of Alzheimer’s disease (AD) is thought to start 10 to 20 years before the onset of the first clinical symptoms in both sporadic and familial forms of the disease. Thus, disease-modifying drugs will most likely be effective when given at a preclinical stage of disease before neurodegeneration has become severe enough to induce clinical symptoms. Amyloid-β (Aβ) peptide and Tau protein, the constituents of the pathological hallmarks of AD, amyloid plaques and neurofibrillary tangles, respectively, have shown promise as markers in cerebrospinal fluid (CSF) of early, preclinical AD. Transgenic mice overexpressing human amyloid precursor protein (APP) have been used to model Aβ pathology, but CSF markers have not been investigated. To this end, Maia et al. optimized methods for collecting mouse CSF and validated sensitive assays for detecting Aβ peptides and total Tau in mouse CSF. They then used these assays to measure Aβ peptides and total Tau in the CSF of two different APP transgenic mouse models, with different ages of onset and progression of Aβ pathology. They found that the Aβ42 concentration in mouse CSF decreased as Aβ deposition started and that CSF t-Tau increased when amyloid plaques in mouse brain became prominent. Mechanistically, these results suggest that Aβ deposition in the brain may be the driving force for changes in Aβ and Tau in the CSF of AD patients. They also suggest the translational value of APP mouse models for understanding events in human disease. Altered concentrations of amyloid-β (Aβ) peptide and Tau protein in the cerebrospinal fluid (CSF) are thought to be predictive markers for Alzheimer’s disease (AD). Transgenic mice overexpressing human amyloid precursor protein (APP) have been used to model Aβ pathology, but concomitant changes in Aβ and Tau in CSF have been less well studied. We measured Aβ and Tau in the brains and CSF of two well-characterized transgenic mouse models of AD: one expressing human APP carrying the Swedish mutation (APP23) and the other expressing mutant human APP and mutant human presenilin-1 (APPPS1). Both mouse models exhibit Aβ deposition in the brain, but with different onset and progression trajectories. We found an age-related 50 to 80% decrease in Aβ42 peptide in mouse CSF and a smaller decrease in Aβ40, both inversely correlated with the brain Aβ load. Surprisingly, the same mice showed a threefold increase in total endogenous murine Tau in CSF at the stages when Aβ pathology became prominent. The results mirror the temporal sequence and magnitude of Aβ and Tau changes in the CSF of patients with sporadic and dominantly inherited AD. This observation indicates that APP transgenic mice may be useful as a translational tool for predicting changes in Aβ and Tau markers in the CSF of AD patients. These findings also suggest that APP transgenic mouse models may be useful in the search for new disease markers for AD.

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