Current disease-modifying therapeutic approaches for Alzheimer´s disease (AD) and Parkinson´s disease (PD) target the formation of the characteristic proteopathic lesions (α-synuclein, Tau, Aβ). To monitor such treatments, fluid biomarkers reflecting the underlying disease process are of crucial importance. Genetically-induced mouse models that develop α-synuclein, Tau, or Aβ lesions are ideally suited for the required translational studies comparing biomarker changes directly with the brain pathology as they avoid the diagnostic uncertainty and interfering comorbidities frequently present in humans. We now report very robust increases of neurofilament light chain (NfL) ranging from 10 to 1000- and 3 to 100-fold in CSF and blood plasma, respectively, in murine models of α-synucleinopathies, taupathy, and ß-amyloidosis. Blood and CSF NfL levels showed a strong correlation and NfL changes coincided with the onset and correlated in magnitude with the corresponding proteopathic lesions in brain. Experimental induction of α-synuclein lesions in α-synuclein transgenic mice increased both CSF and blood NfL levels, while BACE1 inhibition in Aβ precursor protein transgenic mice prevented Aβ lesions and the concomitant increase of NfL in CSF and blood. Our results suggest that CSF and in particular blood NfL can serve as reliable and easily accessible biomarker to monitor disease progression and treatment response in mouse models developing proteopathic lesions and potentially also in AD and PD patients.