RELATIONSHIP OF AMYLOID-BETA A4 PROTEIN TO THE NEUROFIBRILLARY TANGLES IN GUAMANIAN PARKINSONISM-DEMENTIA

The Chamorro population of the island of Guam is highly susceptible to a disease called lytico-bodig (LB), which clinically resembles a mixt ure of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) a nd Alzheimer disease (AD). The disease is characterized by the widespr ead development of neurofibrillary tangles in the central nervous syst em. These tangles have an immunohistochemical profile indistinguishabl e from that seen in AD. We studied by immunohistochemistry the occurre nce of intracellular and extracellular neurofibrillary tangles in LB i n the entorhinal cortex, hippocampus and substantia nigra using antibo dies to tau protein and ubiquitin. We also studied the relationship of these tangles to amyloid precursor protein (APP) and its beta-amyloid fragment (BAP), using multiple antibodies to BAP and other APP sequen ces. In advanced cases of LB, the development of neurofibrillary tangl es was far more severe than in advanced cases of AD. Virtually all neu rons of CA-1 and the subiculum were lost and only ghost tangles remain ed. In areas dominated by such extracellular tangles, BAP deposits wer e frequently observed developing around the fibers of ghost tangles. I n some cases, the deposits covered only a few of the fibers, but in ot hers, they seemed to envelope the complete tangle. The deposits were t hioflavin S and Congo red positive, indicating that the BAP was in a c onsolidated form. We describe these entities as ''tangle-associated am yloid deposits''. Such BAP deposits have previously been described in some cases of AD, dementia pugilistica and LB. However, we found them in all cases of LB with dementia in the hippocampal-entorhinal areas a nd in most cases in the substantia nigra. They do not evolve from diff use BAP deposits since they are remote from them, and they do not trap dystrophic neurites. The fact that extracellular tangle material can act as a nidus for BAP build-up in LB suggests that further considerat ion needs to be given to the ways in which extracellular BAP deposits are formed.