Amyloid β Protein Gene: cDNA, mRNA Distribution, and Genetic Linkage Near the Alzheimer Locus

Tanzi, Rudolph E.; Gusella, James F.; Watkins, Paul C.; Bruns, G. A. P.; George-Hyslop, P. St.; Keuren, Margaret L. Van; Patterson, David; Pagán, Sylvia M; Kurnit, David M.; Neve, Rachael L.

doi:10.1126/science.2949367

Cited by 1,496 publications

(628 citation statements)

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“…It should be noted that the existence of chromosomal imbalance in Alzheimer's disease has been proposed previously (Potter, 1991) on the basis of the location of the ␤APP gene on chromosome 21 (Kang et al, 1987;Tanzi et al, 1987) and the early onset of Alzheimer's disease-like pathology in the brains of patients with Down's syndrome (trisomy 21). In support of this hypothesis, abnormal segregation of chromosomes has been reported in fibroblast cells bearing certain presenilin-1 mutations (Li et al, 1997;Geller and Potter, 1999).…”

Section: Discussionmentioning

confidence: 99%

DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

2001

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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. Key words: cell cycle; PCNA; cyclin B; hippocampus; nucleus basalis; FISH (fluorescent in situ hybridization); neurodegenerationThe death of nerve cells during early development is a constructive part of pruning and shaping the emerging nervous system. The loss of neurons during adult life, however, is a pathological process that produces behavioral disorders and potentially the death of the organism. Recently, several laboratories have offered evidence that an attempt by the cell to reenter a mitotic cycle precedes many instances of neuronal death (Smith and Lippa, 1995;Arendt et al., 1996Arendt et al., , 1998aVincent et al., 1996Vincent et al., , 1997Vincent et al., , 1998McShea et al., 1997McShea et al., , 1999Nagy et al., 1997aNagy et al., , 1998Busser et al., 1998;Smith et al., 1999). Together, these studies suggest that the paradoxical association of the generative process of cell division with the degenerative process of cell death is found at all stages of the existence of a neuron. The prohibition against cell division begins at the earliest stages of maturation of a neuron. Hindbrain neurons in mice lacking the retinoblastoma tumor suppressor gene are unable to avoid reentering the cell cycle and die by apoptosis immediately after their emigration from the ventricular zone (Lee et al., 1994). Neuronal cell death later in development has also been linked to ectopic cell cycling. Using mutant models of target-related cell death, Herrup and Busser (1995) showed that target-deprived neurons initiated the synthesis of cell cycle enzymes [cyclin D and proliferating cell nuclear antigen (PCNA)] and incorporated bromodeoxyuridine (BrdU) into high molecular weight DN...

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Section: Discussionmentioning

confidence: 99%

DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

2001

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“…This hypothesis emphasizes the importance of β-amyloid (Aβ), the major component of senile plaques [2], as an upstream factor in AD pathogenesis, and posits that Aβ initiates a cascade of toxicity, which recruits tau, the major component of tangles in AD pathology [3], and consequently causes neuronal dysfunction, neurotransmitter deficits, and, ultimately, neuron death. Aβ is generated by cleavage of amyloid precursor protein (APP) [4], which can occur via 2 sequential pathways: the nonamyloidogenic and amyloidogenic pathways. The first cleavage event, by α-secretase or β-secretase, determines whether Aβ is generated; the proceeding cleavage by γ-secretase determines the species of Aβ to be generated.…”

Section: Introductionmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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“…2). It is likely that trisomy 21 also causes AD by enhancing amyloid deposition since patients with trisomy 21 have an extra copy of the /3APP gene and show increased expression of /3APP (Tanzi et al 1987) which is normally processed to release A/3.…”

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confidence: 99%

The Amyloid .BETA. Protein Precursor Mutations Linked to Familial Alzheimer's Disease Alter Processing in a Way That Fosters Amyloid Deposition.

Younkin

1994

Tohoku J. Exp. Med.

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Amyloid β Protein Gene: cDNA, mRNA Distribution, and Genetic Linkage Near the Alzheimer Locus

Cited by 1,496 publications

References 34 publications

DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

Biometals and Their Therapeutic Implications in Alzheimer's Disease

The Amyloid .BETA. Protein Precursor Mutations Linked to Familial Alzheimer's Disease Alter Processing in a Way That Fosters Amyloid Deposition.

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