8 January 2001. Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico.
At this meeting, the speakers discussed the sequence of changes in gene expression in the brain that may take place during the transition from normal cognitive functioning to the earliest stages of Alzheimer's disease, focusing in particular on the uniqueness of microarray DNA techniques to monitor several thousands of genes simultaneously with the advantage of providing information on many gene family functions for which information is currently not available in the context of the biological system investigated. The panel reviewed recent and ongoing DNA array studies showing that distinctive gene expression patterns were found at different stages of the clinical progression of Alzheimer's disease dementia. Overall the take-home message from the panel was that important information relevant to the design of effective preventive interventions for Alzheimer's disease could indeed be obtained by a systematic analysis of brain gene expression using DNA microarray techniques.
Jonathan Pevsner, Department of Neuroscience at the Kennedy Krieger Institute at Johns Hopkins University, discussed the suitability of microarray techniques in gene discovery studies of brain pathology. In many disorders of the human brain such as Alzheimer's disease, autism, schizophrenia, and mental retardation, the primary defects are not known. Additionally, a variety of secondary changes in gene expression may occur in these diseases as the brain compensates for the disruption of some pathway perturbed by the primary defect(s). For human disorders that affect cognition or other higher mental functions such as language skills, animal models may be inadequate because they cannot accurately represent the pathological changes. In addition, human brain biopsy material is not available except in extreme cases involving invasive surgery. Thus, an important approach to studying human brain disorders is to analyze postmortem brain samples. Dr. Pevsner discussed recent gene array studies in the brain from patients with autistic disorder and a related pervasive developmental disorder, Rett's syndrome. Using the Atlas (CLONTECH Laboratories), Micromax (NEN Life Sciences) and UniGEM V (Incyte Pharmaceuticals) cDNA microarray chips allowing the analysis of up to 9,000 genes, Dr. Pevsner presented studies exploring differences in gene expression profiles based upon factors such as age at death, gender, brain region, and postmortem interval (PMI). Dr. Pevsner's data indicated that PMI interval is not necessarily a major obstacle for consistency of microarray results across multiple individual postmortem brains. Moreover, he presented convincing evidence suggesting an up-regulation of genes encoding glial proteins, and a down-regulation of genes encoding presynaptic markers in brain from Rett's syndrome. Finally, Dr. Pevsner discussed recent evidence suggesting selective up-regulation of genes encoding receptors and transporters involved in glutamatergic neurotransmission in brain of cases with autism.
Dr. Giulio Maria Pasinetti (author of this symposium report) discussed recent data of a study in which gene activities at specific clinical stages of Alzheimer's disease (AD) were studied using cDNA microarrays. Dr. Pasinetti's laboratory used the high throughput cDNA microarray hybridization methodology to explore the sequence of changes in gene expression in brain, which may influence the onset and progression of early AD dementia. Dr. Pasinetti reported the identification of multiple abnormally regulated genes in brain of cases characterized by early AD dementia. In particular, Dr. Pasinetti presented evidence that the expression of the vesicle-associated protein synapsin IIa, which plays an important role in synaptic vesicle exocytosis, selectively decreases in brain during the conversion from normal cognitive status through the very early stage of cognitive impairment, even before the cases fit the criteria for the clinical diagnosis of probable AD (Ho et al., Neurosci Lett. 2001, in press). The altered expression of synapsin IIa was selective since synapsin IIb and synaptophysin showed no altered expression. Dr. Pasinetti concluded that in the brain of cases at high risk for Alzheimer's disease, while synapses may be morphologically intact, they might be functionally impaired. Dr. Pasinetti proposed that the identification of altered gene expression at the very-early stage of the AD dementia provides a novel experimental framework for strategies leading to the improved diagnosis, treatment and the eventual prevention of AD.
Dr. Stavros Therianos, University of Rochester Medical Center, who replaced Dr. Paul Coleman in the program, presented molecular evidence indicating there is progressive loss of synapses in living neurons, which may play an important role for potential defects in synaptic vesicle recycling and for the involvement of selected genes in the death of neurons in Alzheimer's disease. Dr. Therianos indicated that neurons could survive for an extended period during which they are probably not functioning normally, and losing synapses as their neuritic arbor is retracting. Dr. Therianos proposed that the amount of synaptic loss represents indeed the best correlate of the degree of dementia in Alzheimer's disease, consistent with Dr. Pasinetti's presentation. In addition to the loss of structural synapses in AD, Dr. Therianos discussed recent evidence supporting the hypothesis that even the remaining synapses in brain regions at high risk during AD may be structurally present but become progressively dysfunctional as the disease progresses. Dr. Therianos concluded by discussing three potential scenarios which may explain potential mechanisms leading to synapse loss or dysfunction in AD: 1) loss of synapses through neuron death, 2) loss of synapses made by still living neurons, and 3) malfunction of synapses that are morphologically present.
Finally, Dr. Stefanie Fuhrman, Neurobiology Department at Incyte Genomics, Inc., Palo Alto, presented evidence that large-scale gene expression assay technologies, such as DNA microarrays, may provide an opportunity to measure the expression of many genes over multiple time points, conditions, or anatomical regions. Dr. Furham's presentation brought to focus the study of degenerative disease models, which can be examined at multiple stages in order to gain an understanding of the entire degenerative process. In particular, Dr. Furham used this technology to assay the expression of thousands of genes in a rat amyloid-β toxicity model of Alzheimer's disease (AD). This model involves the unilateral intra-amygdaloid injection of amyloid-beta 25-35 in male rats. Dr. Furham presented evidence that many genes exhibited parallel temporal expression patterns across brain regions in response to Aβ toxicity. In addition, Dr. Furham presented bioinformatics analysis revealing high levels of gene expression "activity" for genes known to be associated with AD, including apolipoprotein E, LDL receptor, MHC Class II, and SNAP-25, as well as for genes with no known relation to Alzheimer's disease.-Giulio Maria Pasinetti, Associate Professor and Director,
Neuroinflammation Research Center, Department of Psychiatry, The Mount Sinai School of Medicine.