Karl Herrup

RAG-1-deficient mice have no mature B and T lymphocytes

The V(D)J recombination activation gene RAG-1 was isolated on the basis of its ability to activate V(D)J recombination on an artificial substrate in fibroblasts. This property and the expression pattern in tissues and cell lines indicate that RAG-1 either activates or catalyzes the V(D)J recombination reaction of immunoglobulin and T cell receptor genes. We here describe the introduction of a mutation in RAG-1 into the germline of mice via gene targeting in embryonic stem cells. RAG-1-deficient mice have small lymphoid organs that do not contain mature B and T lymphocytes. The arrest of B and T cell differentiation occurs at an early stage and correlates with the inability to perform V(D)J recombination. The immune system of the RAG-1 mutant mice can be described as that of nonleaky scid mice. Although RAG-1 expression has been reported in the central nervous system of the mouse, no obvious neuroanatomical or behavioral abnormalities have been found in the RAG-1-deficient mice.

Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice

mGluR1 mutant mice are viable but show characteristic cerebellar symptoms such as ataxic gait and intention tremor. The anatomy of the cerebellum is not overtly disturbed. Excitatory synaptic transmission from parallel fibers (PFs) to Purkinje cells and that from climbing fibers (CFs) to Purkinje cells appear to be functional, and voltage-gated Ca2+ channels of Purkinje cells are normal. Both PF and CF synapses display normal short-term synaptic plasticity to paired stimuli. By marked contrast, long-term depression (LTD) is clearly deficient and conditioned eyeblink response is impaired. We conclude that mGluR1 is required for the induction of LTD and that the ataxic behavior and impaired eyeblink conditioning of the mGluR1 mutant mice are primarily due to deficient LTD.

Ectopic Cell Cycle Proteins Predict the Sites of Neuronal Cell Death in Alzheimer’s Disease Brain

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.

Social Interaction and Sensorimotor Gating Abnormalities in Mice Lacking Dvl1

Mice completely deficient for Dvl1, one of three mouse homologs of the Drosophila segment polarity gene Dishevelled, were created by gene targeting. Dvl1-deficient mice are viable, fertile, and structurally normal. Surprisingly, these mice exhibited reduced social interaction, including differences in whisker trimming, deficits in nest-building, less huddling contact during home cage sleeping, and subordinate responses in a social dominance test. Sensorimotor gating was abnormal, as measured by deficits in prepulse inhibition of acoustic and tactile startle. Thus, Dvl1 mutants may provide a model for aspects of several human psychiatric disorders. These results are consistent with an interpretation that common genetic mechanisms underlie abnormal social behavior and sensorimotor gating deficits and implicate Dvl1 in processes underlying complex behaviors.

Neuronal Cell Death Is Preceded by Cell Cycle Events at All Stages of Alzheimer's Disease

Cell cycle events play a major role in the loss of neurons in advanced Alzheimers disease (AD). It is currently unknown, however, whether the same is true for the neuronal losses in early disease stages. To explore this issue we analyzed brain autopsy material from individuals clinically categorized with mild cognitive impairment (MCI), many if not most of whom will progress to AD. Immunocytochemistry for three cell cycle-related proteins, proliferating cell nuclear antigen, cyclin D, and cyclin B, was performed on sections from hippocampus, basal nucleus of Meynert, and entorhinal cortex. The results obtained from MCI cases were compared with material from individuals diagnosed with AD and those without cognitive impairment. In both hippocampus and basal nucleus, there was a significant percentage of cell cycle immunopositive neurons in the MCI cases. These percentages were similar to those found in the AD cases but significantly higher than non-cognitively impaired controls. In entorhinal cortex, the density of cell cycle-positive neurons was greater in MCI than in AD. However, we observed large variations in the percentages of immunopositive neurons from individual to individual. These findings lend support to the hypothesis that both the mechanism of cell loss (a cell cycle-induced death) and the rate of cell loss (a slow atrophy over several months) are identical at all stages of the AD disease process. The implication of the findings for human clinical trials is discussed.

Cell cycle regulation in the postmitotic neuron: oxymoron or new biology?

Adult CNS neurons are typically described as permanently postmitotic but there is probably nothing permanent about the neuronal cell cycle arrest. Rather, it appears that these highly differentiated cells must constantly keep their cell cycle in check. Relaxation of this vigilance leads to the initiation of a cell cycle and entrance into an altered and vulnerable state, often leading to death. There is evidence that neurons which are at risk of neurodegeneration are also at risk of re-initiating a cell cycle process that involves the expression of cell cycle proteins and DNA replication. Failure of cell cycle regulation might be a root cause of several neurodegenerative disorders and a final common pathway for others.

Reimagining Alzheimer's Disease—An Age-Based Hypothesis

The historical roots of Alzheimers disease provide a sound conceptual basis for linking the behavioral and neurological symptoms of the disease with the frequently associated pathology of amyloid plaques and neurofibrillary tangles. Out of these roots has grown the “amyloid cascade hypothesis”—a vision of the etiology of Alzheimers that has spurred the discovery of many important insights into the neurobiology of the disease. Despite these successes, the wealth of new data now available to biomedical researchers urges a full review of the origins of Alzheimers, and such a reconsideration is offered here. It begins with the most widely accepted risk factor for developing Alzheimers disease: age. Then, for an individual to progress from normal age-appropriate cognitive function to a condition where the full palette of clinical symptoms is expressed, three key steps are envisioned: (1) an initiating injury, (2) a chronic neuroinflammatory response, and (3) a discontinuous cellular change of state involving most, if not all, of the cell types of the brain. The amyloid cascade is integrated into this sequence, but reconfigured as an amyloid deposition cycle. In this way, the pathology of amyloid plaques is envisioned as highly correlated with, but mechanistically distinct from, the three obligatory steps leading to Alzheimers disease. The implications of this new model are discussed with respect to our current diagnostic criteria, and suggestions are put forward for expanding our future research efforts.

Divide and Die: Cell Cycle Events as Triggers of Nerve Cell Death

For over a decade, evidence has mounted that nerve cell death in the CNS is often intimately linked to a process of cell division. Mitotic markers appear in neurons at risk for death in a variety of neurodegenerative conditions, in mouse and in humans. Beyond correlation, studies have shown that

The case for rejecting the amyloid cascade hypothesis

Alzheimers 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.

Interaction of granule, purkinje and inferior olivary neurons in lurcher chimeric mice. II. Granule cell death.

Lurcher in equilibrium ichthyosis chimeric mice were constructed to determine whether the death of cerebellar granule cells in lurcher mutants is caused by intrinsic or extrinsic factors. Quantitative analysis demonstrates that more lurcher granule cells survive in the chimeras than would have in the mutants themselves. Thus the granule cell death is an indirect consequence of the lurcher gene acting on some other cell type, probably the cerebellar Purkinje cells.