Serum Levels of Progranulin Do Not Reflect Cerebrospinal Fluid Levels in Neurodegenerative Disease.

Altered progranulin levels play a major role in neurodegenerative diseases, like Alzheimer's dementia (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), even in the absence of GRN mutations. Increasing progranulin levels could hereby provide a novel treatment strategy. However, knowledge on progranulin regulation in neurodegenerative diseases remains limited. We here demonstrate that cerebrospinal fluid progranulin levels do not correlate with its serum levels in AD, FTD and ALS, indicating a differential regulation of its central and peripheral levels in neurodegeneration. Blood progranulin levels thus do not reliably predict central nervous progranulin levels and their response to future progranulin-increasing therapeutics.

Changes in amyloid-ß and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein.

Altered concentrations of amyloid-ß (Aß) 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 Aß pathology, but concomitant changes in Aß and Tau in CSF have been less well studied. We measured Aß 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 Aß deposition in the brain, but with different onset and progression trajectories. We found an age-related 50 to 80% decrease in Aß42 peptide in mouse CSF and a smaller decrease in Aß40, both inversely correlated with the brain Aß load. Surprisingly, the same mice showed a threefold increase in total endogenous murine Tau in CSF at the stages when Aß pathology became prominent. The results mirror the temporal sequence and magnitude of Aß 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 Aß 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.