The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice.

To test whether the hypothesis that the Alzheimer's A beta peptide is neurotoxic, we introduced a transgene into mice to direct expression of this peptide to neurons. We show that the transgene is expressed in brain regions which are severely affected in Alzheimer's disease resulting in extensive neuronal degeneration. Morphological and biochemical evidence indicates that the eventual death of these cells occurs by apoptosis. Coincident with the cell degeneration and cell death is the presence of a striking reactive gliosis. Over 50% of the transgenic mice die by 12 months of age, half the normal life span of control mice. These data show that A beta is neurotoxic in vivo and suggest that apoptosis may be responsible for the accompanying neuronal loss, the principal underlying cellular feature of Alzheimer's disease.

Complete rescue of photoreceptor dysplasia and degeneration in transgenic retinal degeneration slow (rds) mice.

retinal degeneration slow (rds) is a semidominant mutation of mice with the phenotype of abnormal development of rod and cone photoreceptors, followed by their slow degeneration. The rds gene has been putatively cloned and its novel protein product initially characterized biochemically. In the present study we undertook to correct in vivo the retinal phenotype of mice with the rds mutation. We assembled a transgene containing a regulatory segment of the opsin gene positioned upstream of the wild-type rds coding region. Mice from three transgenic lines, homozygous for the rds mutation, were analyzed for expression of the transgene and for their retinal phenotypes. In two high expressing lines, we observed complete reversion to wild-type retinal morphology. In a third, low expressing line, we observed a retinal phenotype intermediate between wild type and rds/rds, suggesting partial rescue of the mutation. These results constitute formal proof that we have cloned the rds gene.

Oncogene expression in retinal horizontal cells of transgenic mice results in a cascade of neurodegeneration.

The phenylethanolamine N-methyltransferase promoter directs the expression of the SV40 T antigen to subsets of amacrine and horizontal neurons of the retina in a line of transgenic mice. T antigen expression begins in these cells during the first postnatal week. The horizontal cells appear to develop normally for another week but then begin to die. Subsequently, most of the horizontal cells disappear from the central and mid retina, resulting in loss of the outer plexiform layer and absence of ribbon synapses between the photoreceptors and bipolar cells. Neuronal transformation occurs only in the peripheral retina. These experiments indicate that horizontal neurons are heterogeneous with respect to susceptibility to transformation and that T antigen expression in a subset of horizontal neurons can be a direct cause of neuronal cell death. Furthermore, critical interdependencies exist between horizontal neurons after retinal neurogenesis is complete.

ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions.

High levels of familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 mutants G93A and G37R were previously shown to mediate disease in mice through an acquired toxic property. We report here that even low levels of another mutant, G85R, cause motor neuron disease characterized by an extremely rapid clinical progression, without changes in SOD1 activity. Initial indicators of disease are astrocytic inclusions that stain intensely with SOD1 antibodies and ubiquitin and SOD1-containing aggregates in motor neurons, features common with some cases of SOD1 mutant-mediated ALS. Astrocytic inclusions escalate markedly as disease progresses, concomitant with a decrease in the glial glutamate transporter (GLT-1). Thus, the G85R SOD1 mutant mediates direct damage to astrocytes, which may promote the nearly synchronous degeneration of motor neurons.

Macrophage dependence of peripheral sensory nerve regeneration: possible involvement of nerve growth factor.

The levels of NGF and NGF receptor mRNA, the degree of macrophage recruitment, and the ability of sensory and motor axons to regenerate were measured in C57BL/Ola mice, in which Wallerian degeneration following a nerve lesion is very slow. Results were compared with those from C57BL/6J and BALB/c mice, in which degeneration is normal. We found that in C57BL/Ola mice, apart from the actual lesion site, recruitment of macrophages was much lower, levels of mRNA for both NGF and its receptor were raised only slightly above normal, and sensory axon regeneration was much impaired. Motor axons regenerated quite well. These results provide in vivo evidence that macrophage recruitment is an important component of NGF synthesis and of sensory (but not motor) axon maintenance and regrowth.

Neurotrophic factors. Switching neurotrophin dependence.

Recent studies have revealed an unexpected switch in the survival requirements of neurons, from one set of neurotrophins to another, during the early stages of target-field innervation.

On neuronal health.

Many recent studies of the degeneration, neuroprotection and regeneration of CNS neurons have departed from previous dichotomous descriptions of neurons as either dead or alive. In this brief article aspects of neuronal health are examined by outlining ways to assess both neuronal resilience and vulnerability to common forms of structural brain insults. According to this theory of neuronal health, neurons exist in a dynamic equilibrium that spans a spectrum of cellular existence, constantly influenced by both extracellular physiological changes and intracellular mechanisms designed to react to external stimuli while maintaining structural integrity. The spectrum between particularly resilient and vulnerable neuronal states is illustrated by experiments in vivo that examine trophic and metabolic fluctuations influencing the likelihood of neuronal death after neuronal insults. Studies show that adult CNS neurons can be protected in vivo by trophic agents or other pharmacological interventions against structural and toxic damage. Conversely, low-level neuronal impairment due to genetic or physiological perturbations can predispose neurons to demise by insults that normally would not cause cell death. The experimental approaches described may help in the study of neuronal pathophysiology, and in investigations towards new treatments for the neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.

Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration.

Sulfated glycoprotein 2 (SGP-2) from rat, and similar molecules from cow, dog, human, pig, ram and quail are known by 11 or more acronyms. SGP-2 is associated with the responses of brain and other tissues to injury; it and related molecules are also normally secreted by the adrenal gland, the liver and the testes. The mRNA of this protein is found in increased levels in Alzheimer's disease. In rats, after perforant path or excitotoxin lesions, levels of the protein or mRNA are elevated in astrocytes, and also in neurons. In rats, brain SGP-2 is regulated by gonadal and adrenal steroids. However, these increases after brain lesions may relate to a function that is associated with the human protein, namely that of inhibiting complement-mediated cell lysis. Other activities suggested for SGP-2 are lipid transport and cell-cell interactions, which are consistent with sequence data that predict binding of dinucleotides, heparin and lipids. The emerging neurobiology of SGP-2 encompasses the subjects of cell death, synaptic remodelling, neuroendocrinology and neurodegenerative diseases.

A radical hypothesis for neurodegeneration.

Point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD-1) gene have been detected in association with familial amyotrophic lateral sclerosis (FALS). SOD clears superoxide radical and is one of the body's principal defense mechanisms against oxygen toxicity. The finding of SOD variants in FALS is consistent with the hypothesis that free radicals contribute to the pathogenesis of FALS, and possibly to the pathogenesis of other neurodegenerative disorders such as Parkinson's disease, in which there is substantial evidence of oxidant stress. The implication of free radicals in the pathogenesis of neurodegenerative disorders raises the possibility that antioxidants might provide neuroprotective therapy.

Rediscovering an old friend, IGF-I: potential use in the treatment of neurodegenerative diseases.

Insulin-like growth factor-I (IGF-I) is a pleiotropic protein that acts on many tissues and organs. As it is one of the major trophic factors in the circulation, its actions in peripheral tissues are well established. It has been used for the treatment of several diseases, including growth deficiency, osteoporosis, catabolic disorders and diabetes. Recent evidence supports the significance of IGF-I in the maintenance of the integrity and homeostasis of the nervous system. The widespread distribution of its receptor allows IGF-I to affect the survival of numerous populations of neurones and glial cells in both the CNS and the PNS. Most recently, a clinical trial has revealed the beneficial effects of IGF-I in amyotrophic lateral-sclerosis (ALS), a degenerative disease of the motoneurones. We review briefly here experimental and clinical information that suggests the potential usefulness of IGF-I in the treatment of certain neurodegenerative diseases, including ALS, Alzheimer's disease, various neuropathies and brain trauma. The rather unique propensity of IGF-I to act on a variety of neuronal cells might provide a general means of reducing or slowing down neuronal losses that occur following various brain insults.

Prospects of transplantation in human neurodegenerative diseases.

Over the past decade experimental data obtained from animals have suggested that restoration or preservation of function through cell transplantation into the CNS might be developed into a useful therapeutic approach in human neurodegenerative disorders. Clinical trials in patients with Parkinson's disease have provided evidence that grafts of fetal dopaminergic neurons can survive and induce functional effects in the human brain, but no treatment based on transplantation is available yet. Initiation of studies of patients with striatal neural grafts in Huntington's disease is supported by findings in animal models, and is motivated by the lack of therapy and the severity of the symptoms in this disorder. Application of cell transplantation to other neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and hereditary ataxia is definitely premature. Further progress can be made only by systematic studies in animals of the scientific issues that can now be defined, but will also require clinical trials in a few well-monitored patients.

The albino retina: an abnormality that provides insight into normal retinal development.

Albino mammals have specific deficits in their retinae and in the pattern of decussation at their optic chiasm, demonstrating that a melanin-related agent is crucial for normal development of the visual system. Although much attention has been paid to chiasmatic abnormality over the past 30 years, little progress has been made in understanding the abnormality. There has now been a shift of attention towards an analysis of the developing albino retina, which is providing significant advances in our understanding of the role played by this melanin-related agent. It is now possible to identify one candidate substance that emanates from the synthetic pathway of melanin that plays a key role in regulating retinal development.

Selective neuronal vulnerability in the hippocampus--a role for gene expression?

Proposed mechanisms of neurodegeneration focus generally on the triggering of toxic biochemical pathways by an increased intracellular concentration of Ca2+. Recent evidence also suggests that Ca2+ causes transcriptional activation of so-called 'cell-death genes'. Efforts to elucidate the basis of selective vulnerability have relied on animal models of delayed neuronal death in the hippocampus. Biochemical and morphological data indicate that delayed neuronal death is a form of programmed cell death, or apoptosis. Observations that specific genes are activated transcriptionally for prolonged times in neuronal populations that are undergoing delayed death suggest that active gene expression is part of the neuronal-death cascade. Although a direct causal role remains to be proven, evidence implicates certain genes in neuronal-death pathways.

The reconstruction of cerebellar circuits.

Repair of adult 'point-to-point' systems by neural grafting is possible only when grafted neurons succeed in synaptically replacing the host's missing neurons, thus re-establishing the anatomical and functional integrity of the impaired circuits. Grafting experiments carried out on the cerebellum of the adult pcd (Purkinje-cell-degeneration) mutant mouse (an animal model of hereditary degenerative ataxia) reveal that embryonic Purkinje cells, by some unknown sorting mechanism, selectively invade the deprived cerebellar cortex. These neurons migrate to their proper domains and, inducing axonal sprouting of specific populations of host neurons, they become integrated synaptically within the pcd cerebellar cortex. However, the re-establishment of the corticonuclear projection is achieved only rarely, and this is the current experimental limit for the complete reconstruction of the cerebellar circuit.

Spinal and bulbar muscular atrophy: a trinucleotide-repeat expansion neurodegenerative disease.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset motor neuronopathy that is caused by expansion of a trinucleotide (CAG) repeat in the androgen-receptor gene. The length of this repeat varies as it is passed down through SBMA families, and correlates inversely with the age of onset of the disease. The motor-neuron degeneration that occurs in this disease is probably caused by a toxic gain of function in the androgen-receptor protein. Subsequent to the identification of the mutation in SBMA, other inherited neurodegenerative diseases have been found to be caused by the expansion of CAG repeats in the coding regions of other genes. Because these diseases probably share a common pathogenesis, investigation of SBMA might help to determine a general mechanism of neuronal degeneration.

Survival factors in retinal degenerations.

Recent experiments on the retina have examined the effectiveness of various factors (e.g. growth factors, neurotrophins and cytokines) for enhancing survival and reducing injury of retinal neurons, such as photoreceptors and ganglion cells, whose death leads to blindness in degenerative retinal diseases. It has also been shown that retinal injury stimulates intrinsic survival mechanisms that promote survival of these neurons.

Inflammation in the nervous system.

Earlier studies on inflammation in the CNS have largely focused on conditions with an immune component. Recent evidence has emerged, however, that the innate, acute inflammatory response in the CNS parenchyma is quite unlike that in other tissues. The meninges and ventricular compartments show more typical responses, as does the parenchyma of the brain in immature animals. It is becoming apparent that the cells of the mononuclear phagocyte lineage dominate inflammatory responses in the CNS parenchyma.

Peripheral neuropathies and neurotrophic factors: animal models and clinical perspectives.

A large body of data exists showing that a wide variety of neurotrophic factors can promote the survival or growth of different neuronal populations in vitro. More recently, several studies have been published on the survival-promoting effects of particular factors in animal models of peripheral neuropathies. Thus, the effect of axotomy on neuropeptide expression in dorsal root ganglion cells is partially reversed by nerve growth factor treatment, and the effect on choline acetyltransferase expression in motoneurones is partially reversed by glial-derived neurotrophic factor, neurotrophin-4/5 and brain-derived neurotrophic factor. Nerve growth factor also ameliorates some of the changes seen in sensory neurones in animal models of diabetic neuropathy and small fibre cytostatic drug neuropathy, whereas neurotrophin-3 has been found to reverse some changes in large sensory neurones associated with cisplatin neurotoxicity. The results of these studies provide grounds for optimism in the clinical uses of such factors, and, indeed, several clinical studies are now under way.

Genetic linkage studies of human neurodegenerative disorders.

Recombinant DNA technology has the ability to delineate the causes of several neurodegenerative disorders. Genetic linkage studies have been used successfully to localize gene defects and it is likely that in the near future the exact loci will be determined.