EXPERIMENTALLY-INDUCED LYSOSOMAL DYSFUNCTION DISRUPTS PROCESSING OF HYPOTHALAMIC RELEASING FACTORS

Previous studies have shown that experimentally induced lysosomal dysf unction elicits various features of aging in the cortical telencephalo n. The present study used cultured slices to test if: (1) it causes si milar changes in the hypothalamus, and/or (2) modifies the processing of two releasing factors important to aging. A 2-day exposure to N-CBZ -L-phenylalanyl-L-alanine-diazomethylketone (ZPAD), a selective inhibi tor of cathepsins B and L, triggered a pronounced increase in the numb ers of lysosomes in the ventromedial and dorsomedial nuclei, and in la teral hypothalamus. Continued incubation with the inhibitor for 3-12 d ays resulted in the spread of endosomes-lysosomes into dendrites and, in the lateral hypothalamus, the formation of massive, lysosome-filled expansions of neuronal processes (meganeurites). These effects did no t occur in the arcuate nucleus, making it the first region so far exam ined in which lysosomal proliferation is not initiated by hydrolase in hibitors. Despite this, a dense plexus of axons and terminals in the m edian eminence was partially depleted of growth hormone releasing horm one (GHRH) within 48 hours after addition of ZPAD. Moreover, the inhib itor caused axonal GHRH to become collected into large puncta, an effe ct highly suggestive of a partial failure in axonal transport. GHRH mR NA levels were not greatly affected by 6 days of ZPAD exposure, indica ting that reduced expression did not play a major role in the peptide changes seen at 48 hours. Similar but less pronounced immunocytochemic al changes were recorded for the somatostatin system in the arcuate an d periventricular nucleus. It is concluded that lysosome dysfunction: (1) has different consequences for the arcuate nucleus than other brai n regions, and (2) disrupts transport of hypothalamic releasing factor s. The potential significance of the results to endocrine senescence i s discussed. J. Comp. Neurol. 401:382-394, 1998. (C) 1998 Wiley-Liss, Inc.