Broadly altered expression of the mRNA isoforms of FE65, a facilitator of beta amyloidogenesis, in Alzheimer cerebellum and other brain regions

FE65 is a key "adapter" protein that links a multiprotein complex to an int racellular domain of beta-amyloid precursor protein (beta PP). Its overexpr ession modulates the trafficking of beta PP and facilitates the generation of beta-amyloid (A beta). FE65 is predominantly expressed in brain tissues. An exon 9-inclusive isoform is exclusively expressed in neurons, and an ex on 9-exclusive isoform is only expressed in non-neuronal cells. We quantita ted the two isoforms in middle temporal cortex, middle frontal cortex, cere bellar cortex and caudate nucleus of 17 Alzheimer disease (AD) patients, 12 normal controls and 9 non-AD neurodegenerative disease controls by reverse transcription-competitive polymerase chain reaction (RT-cPCR). Expression of the two isoforms was significantly and differentially altered, with a 30 -57% decrease in levels of the neuronal form (P < 0.05 0.002) and a 73-135% increase in levels of nonneuronal form (P < 0.02-0.001), in the temporal a nd frontal cortex of AD brains. These alterations presumably reflect advanc ed neurodegenerative processes of these regions. Surprisingly, expression o f both isoforms was significantly up-regulated by 42-66% in the cerebellar cortex and caudate nucleus of AD brains when compared to normal brains (P < 0.05-0.005). Diffuse A beta-positive plaques were observed in the cerebell um of these AD subjects but not in the normal controls. Selective up-regula tion of only the FE65 neuronal isoform was seen in the cerebellar cortex in association with other neurodegenerative diseases (largely Parkinson's dis ease), Because FE65 modulates trafficking of beta PP toward the production of A beta, the up-regulation of FE65 in AD cerebellum may be relevant to th e genesis of diffuse plaques. Thus, early biochemical alterations in AD, no t complicated by advanced pathology, may be beneficially investigated in th e less-affected regions of the brain, such as the cerebellum. J. Neurosci. Res. 60:73-86, 2000. (C) 2000 Wiley-Liss, Inc.