ELEVATED LEVELS OF THE ENDOSOMAL-LYSOSOMAL PROTEINASE CATHEPSIN-D IN CEREBROSPINAL-FLUID IN ALZHEIMER-DISEASE

Lysosomal hydrolases are normally intracellular enzymes but are abunda nt extracellularly within senile plaques in Alzheimer disease and in o ther conditions where beta-amyloid accumulates. To examine whether aci d hydrolases released from abnormal hydrolase-laden neurons are detect able in CSF, we measured levels of the major aspartic proteinase of ly sosomes, cathepsin D (Cat D), in Ventricular CSF collected after death from 30 patients with Alzheimer disease, 14 patients with Huntington disease, and seven patients with other neurodegenerative diseases. The levels of Cat D-immunoreactive protein, expressed as micrograms per m illiliter of protein, determined by western blot immunoassay using a p olyclonal antiserum against human brain Cat D, were more than fourfold higher in the Alzheimer patients than in the other patient groups (p < 0.0005). Cat D activity, assayed separately against [C-14]methemoglo bin at pH 3.2, was also significantly elevated but less than Cat D con tent. The tower specific activity of Cat D in Alzheimer CSF therefore indicated that the abnormally accumulated Cat D included a high propor tion of inactive enzyme. These results indicate that abnormal Cat D re lease from affected neurons into the extracellular space is an active, ongoing process in Alzheimer brain. In addition, the levels of this e nzyme and possibly other lysosomal hydrolases in CSF may prove to be u seful biological markers of Alzheimer disease.