Neuronal activity and early neurofibrillary tangles in Alzheimer's disease.
We studied neuronal activity and its relation to the accumulation of neurofibrillary tangles in Alzheimer's disease (AD) neurons by in situ hybridization to cytochrome oxidase subunit III messenger RNA, a marker of mitochondrial energy metabolism. In AD midtemporal cortex, levels of cytochrome oxidase subunit III messenger RNA were decreased by 26% in neurons bearing early-stage neurofibrillary tangles as compared to tangle-free neurons (p < 0.01). However, levels of 12S ribosomal RNA, also encoded by mitochondrial DNA, and of total messenger RNA were decreased only in later stages of tangle development. Comparing tangle-free neurons of 4 AD brains to tangle-free neurons of 3 control brains, levels of cytochrome oxidase subunit III messenger RNA were found to be 25% lower (p < 0.001) in AD tangle-free neurons. Because energy metabolic needs of neurons are mainly determined by synaptic input, the observed decreases in cytochrome oxidase subunit III messenger RNA likely reflect downregulation due to impaired synaptic function in AD. Thus, a failure in synaptic transmission may precede tangle formation. A further decline in neuronal activity is seen as tangle formation progresses. However, these results can also be viewed as showing the viability and continuing activity, albeit at a lower level, of neurons in the early stages of neurofibrillary pathology.
Hatanpää
K
K
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892-1582, USA.
Brady
D R
DR
Stoll
J
J
Rapoport
S I
SI
Chandrasekaran
K
K
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003576:Electron Transport Complex IV / Q000235:genetics; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000473:pathology*; D009474:Neurons / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D013702:Temporal Lobe / Q000378:metabolism
D007527:Isoenzymes; D015335:Molecular Probes; D012333:RNA, Messenger; D003576:Electron Transport Complex IV