Frameshifted beta-amyloid precursor protein (APP(+1)) is a secretory protein, and the level of APP(+1) in cerebrospinal fluid is linked to Alzheimer pathology

Molecular misreading of the beta-amyloid precursor protein (APP) gene generates mRNA with dinucleotide deletions in GAGAG motifs. The resulting truncated and partly frameshifted APP protein ( APP(+1)) accumulates in the dystrophic neurites and the neurofibrillary tangles in the cortex and hippocampus of Alzheimer patients. In contrast, we show here that neuronal cells transfected with APP(+1) proficiently secreted APP(+1). Because various secretory APP isoforms are present in cerebrospinal fluid (CSF), this study aimed to determine whether APP(+1) is also a secretory protein that can be detected in CSF. Post-mortem CSF was obtained at autopsy from 50 non-demented controls and 122 Alzheimer patients; all subjects were staged for neuropathology (Braak score). Unexpectedly, we found that the APP(+1) level in the CSF of non-demented controls was much higher (1.75 ng/ml) than in the CSF of Alzheimer patients (0.51 ng/ml) ( p <0.001), and the level of APP(+1) in CSF was inversely correlated with the severity of the neuropathology. Moreover the earliest neuropathological changes are already reflected in a significant decrease of the APP(+1) level in CSF. These data show that APP(+1) is normally secreted by neurons, preventing intraneuronal accumulation of APP(+1) in brains of nondemented controls without neurofibrillary pathology