Reported by Paul Coleman
Bradley T. Hyman and Paul D. Coleman, Chairs

This symposium (held 10 July) covered the gamut of age-related evolution of brain function in AD from behavioral studies emphasizing mild cognitive impairment (MCI) presented by Steve Ferris through microscopic structure (John Morrison, Bradley Hyman and Mark West) to events at the cell biological and molecular levels (Eva-Maria Mandelkow and Paul Coleman).

Steve Ferris outlined the battery of psychometric tests being used at the New York University Alzheimer's Disease Center. He presented data indicating that the NYU Paragraph Recall Test was useful in identifying cases at high risk of being diagnosed with AD within several years. In their experience, the rate of conversion from MCI to diagnosed AD was 10%-15% per year-a figure that corresponds exactly to comparable data from Petersen at Mayo Clinic, Minnesota.

This description of behavioral data was followed by three presentations centering on structural aspects of dementia that were not closely related to MCI, but that did deal with structural changes that differentiated AD from normal aging. Mark West outlined the procedures of unbiased stereology for counting total numbers (not density) of neurons and showed data demonstrating that, whereas in AD there was a major loss of neurons in hippocampal CA1, there was no such loss in normal aging. These data led West to conclude that AD is qualitatively different from normal aging and, therefore, not an extension of healthy aging. John Morrison stressed the chemical phenotype of neuron classes that were among the earliest to decline in AD. He reported that neurons expressing the NR1 receptor were exquisitely sensitive indicators of AD pathology. Bradley Hyman demonstrated neuron loss in thioflavin positive plaques, but not in plaques that were not thioflavin positive (see News Report).

The symposium then shifted to a more molecular focus. Eva-Maria Mandelkow presented data from their continuing investigations of the cell biology of tau. She showed data demonstrating that the kinase, MARK, phosphorylates Ser 262 in the microtubule binding domain of tau, as well as KXGS motifs in MAP2 and MAP4. The hyperphosphorylation produced by overexpression of MARK in vitro leads to massive disruption of microtubules and cell death. On the other hand, MARK phosphorylation of KXGS motifs in tau are essential for tau-induced process formation in model cell systems, pointing to the requirement for a delicate balance in MARK activity. Additional studies of the cell biology of tau showed that tau is capable of inhibiting kinesin-dependent transport in the plus direction of microtubules. Tau does not change the speed of transport, but does decrease the probability of attachment of motors to microtubules. In the case of nerve cells mitochondria and other organelles then disappear from the cell processes, which suggested to Mandelkow consequent energy deprivation and vulnerability of cells.

This symposium concluded with a presentation by Paul Coleman of work from his laboratory dealing with message expression of single cells and homogenates in Alzheimer's disease. Quantitative in situ hybridization of synaptophysin message in conjunction with double immunohistochemistry for neurofibrillary tangles and tau phosphorylated at selected epitopes demonstrated an incremental loss of synaptophysin message progressing from immunonegative neurons in control brain to immunonegative neurons in AD brain to tangle-free neurons immunopositive for phospho tau at Ser 262 to neurons with frank neurofibrillary tangles. Phosphorylation at Ser 396/404 resulted in no additional decrement of synaptophysin message in NFT-free neurons. The decreased expression of synaptophysin message was not a consequence of a generalized decrease in message expression since message for cathepsin D was increased in tangle-bearing neurons-in agreement with data of Nixon and Cataldo.

These, and other, demonstrations that although some message levels decrease in AD other message levels increase leads to the concept of changing profiles of gene expression as disease progresses, rather than a generalized decrease of message expression. The advent of array methods to profile expression of message of large numbers of genes, either in homogenates or in single, immunohistochemically defined cells, provides the opportunity to examine these profiles of message expression in greater detail than previously possible. Coleman presented data from some of the array studies from his lab. The general conclusions from these data are: 1) more genes show increased and fewer genes show decreased expression in AD; 2) gene classes showing increased expression in AD include genes related to the cell cycle and genes related to inflammatory processes. Gene classes showing decreased expression in AD include those related to selected aspects of synaptic and cell structure and function and those related to metabolic activities. Note that these latter two classes include genes such as actin and GAPDH which are often used as "control" genes; 3) multivariate statistical analyses separate AD samples from control samples on the basis of expression of appropriate sets of genes.


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