Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment but strongly interacts with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on micro- and astroglia and trigger an innate immune response, characterized by the release of inflammatory mediators, which contribute to disease progression and severity. Genome wide analysis suggests that several genes, which increase the risk for sporadic Alzheimer's disease en-code for factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity are likely to interfere with the immunological processes of the brain and further promote disease progression. This re-view provides an overview on the current knowledge and focuses on the most recent and exciting findings. Modulation of risk factors and intervention with the described immune mechanisms are likely to lead to future preventive or therapeutic strategies for Alzheimer's disease.

No abstract

Gene targeting was used to create a null allele at the epidermal growth factor receptor locus (Egfr). The phenotype was dependent on genetic background. EGFR deficiency on a CF-1 background resulted in peri-implantation death due to degeneration of the inner cell mass. On a 129/Sv background, homozygous mutants died at mid-gestation due to placental defects; on a CD-1 background, the mutants lived for up to 3 weeks and showed abnormalities in skin, kidney, brain, liver, and gastrointestinal tract. The multiple abnormalities associated with EGFR deficiency indicate that the receptor is involved in a wide range of cellular activities.

The retinoblastoma gene, a prototypic tumour-suppressor gene, encodes a nuclear phosphoprotein (Rb). To understand better the role of Rb in development and in tumorigenesis, mice with an insertional mutation in exon 20 of the Rb-1 locus were generated. Homozygous mutants die before the 16th embryonic day with multiple defects. The haematopoietic system is abnormal; there is a significant increase in the number of immature nucleated erythrocytes. In the nervous system, ectopic mitoses and massive cell death are found, particularly in the hindbrain. All spinal ganglion cells die, but the neural retina is unaffected. Transfer of the human retinoblastoma (RB) mini-transgene into the mutant mice corrects the developmental defects. Thus, Rb is essential for normal mouse development.

No abstract

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...

Alzheimer's disease (AD) is a biologically complex neurodegenerative dementia. Nearly 20 years ago, with the combination of observations from biochemistry, neuropathology and genetics, a compelling hypothesis known as the amyloid cascade hypothesis was formulated. The core of this hypothesis is that it is pathological accumulations of amyloid-β, a peptide fragment of a membrane protein called amyloid precursor protein, that act as the root cause of AD and initiate its pathogenesis. Yet, with the passage of time, growing amounts of data have accumulated that are inconsistent with the basically linear structure of this hypothesis. And while there is fear in the field over the consequences of rejecting it outright, clinging to an inaccurate disease model is the option we should fear most. This Perspective explores the proposition that we are over-reliant on amyloid to define and diagnose AD and that the time has come to face our fears and reject the amyloid cascade hypothesis.

Alzheimer's disease (AD) is a major dementing illness characterized by regional concentrations of senile plaques, neurofibrillary tangles, and extensive neuronal cell death. Although cell and synaptic loss is most directly linked to the severity of symptoms, the mechanisms leading to the neuronal death remain unclear. Based on evidence linking neuronal death during development to unexpected reappearance of cell cycle events, we investigated the brains of 12 neuropathologically verified cases of Alzheimer's disease and eight age-matched, disease-free controls for the presence of cell cycle proteins. Aberrant expression of cyclin D, cdk4, proliferating cell nuclear antigen, and cyclin B1 were identified in the hippocampus, subiculum, locus coeruleus, and dorsal raphe nuclei, but not inferotemporal cortex or cerebellum of AD cases. With only one exception, control subjects showed no significant expression of cell cycle markers in any of the six regions. We propose that disregulation of various components of the cell cycle is a significant contributor to regionally specific neuronal death in AD.