Neurons bearing neurofibrillary tangles are responsible for selected synaptic deficits in Alzheimer's disease.
The observation that neurons containing neurofibrillary tangles are usually adjacent to neurons free of any morphological indication of disease, suggests the hypothesis that it is NFT-bearing neurons that are primarily responsible for the loss of function in AD. Quantitative Golgi postmortem studies from our laboratories have indicated that there is in many regions of the brains of nondemented humans an age-related increase in dendritic extent of single neurons. In Alzheimer's disease, this normal, age-related increase in dendritic extent was not found, leading to the hypothesis that one of the neurobiological defects in AD is a failure of neuronal plasticity. Message levels of the growth-associated protein, GAP-43, in frontal association cortex (area 9/46) indicated that AD brains with the highest density of neurofibrillary tangle-bearing neurons, showed GAP-43 message levels decreased of the order of 6-fold relative to AD brains with the lowest density of NFT. Combined immunocytochemistry to differentiate tangle-bearing from tangle-free neurons with in situ hybridization to define relative GAP-43 message levels in single neurons revealed that grain density over tangle-bearing neurons containing nuclei was reduced 3-fold compared to that over adjacent tangle-free neurons. This reduction in expression of GAP-43 message in tangle-bearing neurons was selective, because using probes for other messages showed that grain density over tangle-bearing neurons was, on average, increased or similar to that over adjacent non-tangle-bearing neurons. Message levels for the synaptic vesicle-associated protein, synaptophysin, have also been found to be reduced in tangle-bearing neurons relative to adjacent tangle-free neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Callahan
L M
LM
Department of Neurobiology and Anatomy, University of Rochester Medical Center, NY 14642, USA.
Coleman
P D
PD
D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D019922:GAP-43 Protein; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology; D016874:Neurofibrillary Tangles / Q000473:pathology*; D016900:Neurofilament Proteins / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
D019922:GAP-43 Protein; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins