The brains of Alzheimer's disease patients contain extracellular A␤ amyloid deposits (senile plaques). Although genetic evidence causally links A␤ deposition to the disease, the mechanism by which A␤ disrupts cortical function is unknown. Using triple immunof luorescent confocal microscopy and three-dimensional reconstructions, we found that neuronal processes that cross through an A␤ deposit are likely to have a radically changed morphology. We modeled the electrophysiological effect of this changed morphology and found a predicted delay of several milliseconds over an average plaque. We propose that this type of delay, played out among thousands of plaques throughout neocortical areas, disrupts the precise temporal firing patterns of action potentials, contributing directly to neural system failure and dementia.Alzheimer's disease (AD) causes a clinical syndrome marked by severe, progressive dementia. Neuropathological changes include A␤ deposits that are often associated with dystrophic neurites (neuritic plaques), dystrophic neurites in the neuropil (neuropil threads), and neurofibrillary tangles. Inheritance of mutations in the amyloid protein precursor lead to changes in the generation of A␤, extracellular deposition of A␤ in the brain, and an autosomal dominant early onset form of AD (1-3), suggesting that A␤ is a critical early component of the pathophysiological cascade. However, whether A␤ deposition causes neural system failure is controversial. Brains of nondemented elderly individuals frequently contain numerous A␤ deposits (4). Even in AD, where A␤ deposits can occupy as much as 15% of the cortical surface area, the amount of A␤ deposits correlates poorly with clinical severity or duration of disease (5-7).It has been shown that A␤ deposits do not correlate with local neuronal loss (7,8). We now examine their effect on neuronal processes. We observe that neurites that pass through A␤ deposits in AD lose their normal characteristic straight shape. This change in geometry has marked consequences in terms of signal transduction properties of dendrites as judged by cable-theory simulations; delays in the millisecond range would be expected as a dendrite passes through a plaque. Insofar as any individual process passes through a variable number of plaques en route from synapse to cell body, we postulate that plaques distributed in widespread neocortical areas lead to a disruption of synchronous activation of neural systems and a stochastic breakdown in the integration of limbic and association cortices needed to form coherent evocation of memory-related events (9). MATERIALS AND METHODSPatient Selection. All cases were monitored at the Massachusetts General Hospital Alzheimer's Disease Research Center. Seven patients had clear clinical histories of AD dementia with well documented duration of disease and had a confirmed neuropathological diagnosis of AD without evidence of vascular insults (10), cortical Lewy bodies, or other dementiarelated lesions. General neuropathological examination include...

It is well known that Neuroblastoma (NB) patients whose tumors have an undifferentiated histology and a transcriptome enriched in cell cycle genes have a worse prognosis. This contrasts with the good prognoses of patients whose tumors have histologic evidence of differentiation and a transcriptome enriched in differentiation genes. Tumor cell lines from poor prognosis, high-risk patients contain a number of genetic alterations, including amplification of MYCN, 1pLOH, and unbalanced 11q or gains of Chr 17 and 7, and exhibit uncontrolled growth and an undifferentiated phenotype in in vitro culture. Yet treatment of such NB cell lines with retinoic acid results in growth control and induction of differentiation. This indicates that the signaling pathways that regulate cell growth and differentiation are not functionally lost but dysregulated. Agents such as retinoic acid normalize the signaling pathways and impose growth control and induction of differentiation. Recent studies in embryonic stem cells indicate that polycomb repressor complex proteins (PRC1 and PRC2) play a major role in regulating stem cell lineage specification and coordinating the shift from a transcriptome that supports self-renewal or growth to one that specifies lineage and controls growth. We have shown that in NB, the PRC2 complex is elevated in undifferentiated NB tumors and functions to suppress a number of tumor suppressor genes. This study will review the role of MYC genes in regulating the epigenome in normal development and explore how this role may be altered during tumorigenesis.