LYSOSOMAL DYSFUNCTION REDUCES BRAIN-DERIVED NEUROTROPHIC FACTOR EXPRESSION

Brain-derived neurotrophic factor (BDNF) expression in hippocampus and cortex is considerably reduced in Alzheimer's disease. The present st udy tested if lysosomal disturbances, a concomitant of brain aging, im pair basal and/or induced expression of BDNF. Cultured hippocampal sli ces were incubated with N-CBZ-L-phenylalanyl-L-alanine-diazomethylketo ne (ZPAD), an inhibitor of cathepsins B and L, for 6 days and processe d for in situ hybridization using radiolabeled cRNA probes against BDN F mRNA. Multiple densitometric readings were collected from each of th e three principal hippocampal subdivisions. Within-slice averages were substantially lower in the ZPAD-treated group compared to controls. T reatment with the inhibitor did not change average neuron diameter or packing density. Intense stimulation of glutamate receptors with kaina te for 30 min (followed by a 90-min recovery period) caused a nearly t hreefold increase in BDNF mRNA concentrations in the dentate gyrus whi le having only marginal effects in the other subdivisions. Slice avera ges of ZPAD-exposed cultures treated with kainate were lower than thos e of controls exposed to the excitotoxin; however, on a percentage bas is, the kainate-induced increase in the dentate gyrus was comparable f or the two groups (175 +/- 31 vs 179 +/- 39%). Kainate for 1 h (with a 5-h recovery) affected BDNF mRNA in a manner similar to that found wi th shorter infusions, i.e., induction in stratum granulosum but not el sewhere, lower overall slice averages with ZPAD treatment, and no evid ence that ZPAD blocked the percentage increase in the dentate gyrus. T hese results provide evidence that lysosomal dysfunction occurring dur ing brain aging could disrupt ongoing BDNF production without substant ially impairing the neurotrophin response to intense physiological act ivity. The first observation suggests a plausible aging sequence leadi ng to pathology while the second may be of interest with regard to pos sible therapeutics. (C) 1998 Academic Press.