DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

By Yan Yang, D. Geldmacher, Karl Herrup. Journal of Neuroscience, 2001

618 citations recorded by the source corpus.

Alzheimer's disease (AD) is a devastating dementia of late life that is correlated with a region-specific neuronal cell loss. Despite progress in uncovering many of the factors that contribute to the etiology of the disease, the cause of the nerve cell death remains unknown. One promising theory is that the neurons degenerate because they reenter a lethal cell cycle. This theory receives support from immunocytochemical evidence for the reexpression of several cell cycle-related proteins. Direct proof for DNA replication, however, has been lacking. We report here the use of fluorescent in situ hybridization to examine the chromosomal complement of interphase neuronal nuclei in the adult human brain. We demonstrate that a significant fraction of the hippocampal pyramidal and basal forebrain neurons in AD have fully or partially replicated four separate genetic loci on three different chromosomes. Cells in unaffected regions of the AD brain or in the hippocampus of nondemented age-matched controls show no such anomalies. We conclude that the AD neurons complete a nearly full S phase, but because mitosis is not initiated, the cells remain tetraploid. Quantitative analysis indicates that the genetic imbalance persists for many months before the cells die, and we propose that this imbalance is the direct cause of the neuronal loss in Alzheimer's disease.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/1e8f175bc8b579a6c215c0dd5c06b5db0c1fa09c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. R. Swerdlow
2. Shaharyar M. Khan
3. Fred H. Gage
4. Mark P. Mattson
5. Hongjun Song

In Physiology

1. R. Swerdlow
2. Shaharyar M. Khan
3. Mark P. Mattson
4. Fred H. Gage
5. M. O’Banion
6. Michael T. Heneka

Citations in the corpus

• A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. (2004, background): “AD brain shows evidence of increased apoptotic cell death, cyclin protein expression, and nuclear DNA replication with excess aneuploidy [23–25].”
• Progesterone receptors: form and function in brain. (2008, neutral): “They also found that DNA replication precedes neuronal death in AD brain [304].”
• Neurodegenerative disease and adult neurogenesis (2011, background): “Another possible explanation of these divergent results of increased or decreased proliferation in AD transgenic models might be other responses to damage due to protein overexpression, such as glia activation or aberrant cell cycle changes, as described in other brain regions (Yang et al., 2001; Va”
• Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease (2002, background): “DNA replication can be triggered in postmitotic neurons (Smith et al., 2000; Yang et al., 2001).”
• Neuroplasticity in old age: Sustained fivefold induction of hippocampal neurogenesis by long‐term environmental enrichment (2002, background): “Suggestive links also exist for Alzheimer’s disease.(20,21) All of these conditions share symptoms of hippocampal dysfunction and cognitive alterations, most prominently dementia or pseudodementia.”
• The harlequin mouse mutation downregulates apoptosis-inducing factor (2002, background): “Abnormal expression of cell cycle markers and de novo DNA synthesis in hippocampus, cholinergic basal forebrain and neocortical association areas distinguish post mortem tissue from Alzheimer's disease patients from that of non-Alzheimer's disease subject”