Showing papers by "Donald L. Price published in 1998"

Mutant genes in familial alzheimer's disease and transgenic models

Abstract: The most common cause of dementia occurring in mid- to late-life is Alzheimer's disease (AD). Some cases of AD, particularly those of early onset, are familial and inherited as autosomal dominant disorders linked to the presence of mutant genes that encode the amyloid precursor protein (APP) or the presenilins (PS1 or PS2). These mutant gene products cause dysfunction/death of vulnerable populations of nerve cells important in memory, higher cognitive processes, and behavior. AD affects 7-10% of individuals > 65 years of age and perhaps 40% of individuals > 80 years of age. For the late-onset cases, the principal risk factors are age and apolipoprotein (apoE) allele type, with apoE4 allele being a susceptibility factor. In this review, we briefly discuss the clinical syndrome of AD and the neurobiology/neuropathology of the disease and then focus attention on mutant genes linked to autosomal dominant familial AD (FAD), the biology of the proteins encoded by these genes, and the recent exciting progress in investigations of genetically engineered animal models that express these mutant genes and develop some features of AD.

Alzheimer's disease: genetic studies and transgenic models.

Abstract: Recent advances in a variety of areas of research, particularly in genetics and in transgenic (Tg)/gene targeting approaches, have had a substantial impact on our understanding of Alzheimer's disease (AD) and related disorders. After briefly reviewing the progress that has been made in diagnostic assessments of patients with senile dementia and in investigations of the neuropathology of AD, we discuss some of the genes/proteins that are causative or risk factors for this disease, including those encoding amyloid precursor protein, presenilin 1 and 2, and apolipoprotein E. In addition, we comment on several potential new candidate loci/genes. Subsequently, we review selected recent reports of analyses of a variety of lines of Tg mice that show several neuropathological features of AD, including A beta-amyloid deposits and dystrophic neurites. Finally, we discuss the several important issues in future investigations of Tg mice, with particular emphasis on the influences of genetic strains on phenotype, especially behavior, and strategies for making new models of neurodegenerative disorders. We believe that investigations of these Tg models will (a) enhance understanding of the relationships between impaired performance on memory tasks and the pathological/biochemical abnormalities in brain, (b) help to clarify pathogenic mechanisms in vivo, (c) lead to identification of new therapeutic targets, and (d) allow testing of new treatment strategies first in mice and then, if successful, in humans with AD.

Alzheimer Amyloid Protein Precursor in the Rat Hippocampus: Transport and Processing through the Perforant Path

Abstract: Amyloid deposition is a neuropathological hallmark of Alzheimer’s disease. The principal component of amyloid deposits is β amyloid peptide (Aβ), a peptide derived by proteolytic processing of the amyloid precursor protein (APP). APP is axonally transported by the fast anterograde component. Several studies have indicated that Aβ deposits occur in proximity to neuritic and synaptic profiles. Taken together, these latter observations have suggested that APP, axonally transported to nerve terminals, may be processed to Aβ at those sites. To examine the fate of APP in the CNS, we injected [35S]methionine into the rat entorhinal cortex and examined the trafficking and processing of de novo synthesized APP in the perforant pathway and at presynaptic sites in the hippocampal formation. We report that both full-length and processed APP accumulate at presynaptic terminals of entorhinal neurons. Finally, we demonstrate that at these synaptic sites, C-terminal fragments of APP containing the entire Aβ domain accumulate, suggesting that these species may represent the penultimate precursors of synaptic Aβ.

Genetic neurodegenerative diseases: The human illness and transgenic models

Abstract: Review The neurodegenerative disorders, a heterogeneous group of chronic progressive diseases, are among the most puzzling and devastating illnesses in medicine. Some of these disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, the prion diseases, and Parkinson's disease, can occur sporadically and, in some instances, are caused by inheritance of gene mutations. Huntington's disease is acquired in an entirely genetic manner. Transgenic mice that express disease-causing genes recapitulate many features of these diseases. This review provides an overview of transgenic mouse models of familial amyotrophic lateral sclerosis, familial Alzheimer's disease, and Huntington's disease and the emerging insights relevant to the underlying molecular mechanisms of these diseases.

Protective effect of neurofilament heavy gene overexpression in motor neuron disease induced by mutant superoxide dismutase

Abstract: To investigate the role of neurofilaments in motor neuron disease caused by superoxide dismutase (SOD1) mutations, transgenic mice expressing a amyotrophic lateral sclerosis-linked SOD1 mutant (SOD1G37R) were mated with transgenic mice expressing human neurofilament heavy (NF-H) subunits. Unexpectedly, expression of human NF-H transgenes increased by up to 65%, the mean lifespan of SOD1G37R mice. Microscopic examination corroborated the protective effect of NF-H protein against SOD1 toxicity. Although massive neurodegeneration occurred in 1-yr-old mice expressing SOD1G37R alone, spinal root axons and motor neurons were remarkably spared in doubly SOD1G37R;NF-H-transgenic littermates.

Familial amyotrophic lateral sclerosis and Alzheimer's disease. Transgenic models.

Abstract: Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) are two classical neurodegenerative disorders These age-related, chronic, progressive diseases are accompanied by clinical signs that reflect the vulnerability and death of specific populations of neurons Unfortunately, there are no satisfactory treatments for these diseases Both ALS and AD may be inherited in an autosomal dominant fashion: some cases of familial ALS (FALS) are linked to mutations in Superoxide dismutase 1 (SOD1); and some individuals with familial AD (FAD) have mutations in genes encoding the amyloid precursor protein (APP) or presenilins (PS1 and PS2) Products of these mutant genes, thought to be associated with the formation of improperly folded or processed proteins, impact upon specific subsets of neural cells and cause characteristic clinical manifestations For example, in ALS, damage to upper and lower motor neurons results in spasticity and weakness/muscle atrophy, respectively; in AD, the involvement of a variety of brain regions/neuronal populations is reflected in loss of memory, cognitive/behavioral impairments, and, eventually, profound dementia

Transgenic Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease

Abstract: This chapter describes transgenic (Tg) technologies and discusses the clinical, genetic, and neuropathological features of amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), with particular emphasis on the autosomal dominant forms of these diseases. ALS and familial amyotrophic lateral sclerosis (FALS) are characterized by paralysis, muscular atrophy, spasticity, and a variety of other motor signs, with relative preservation of eye movements, potency, and sphincters. Some mutant superoxide dismutase (SOD1) show normal enzyme activity but acquire neurotoxic properties and in vitro studies have provided information concerning amyloid precursor protein (APP) and presenilin (PS) processing and the effects of mutations on the generation of β-amyloid (Aβ). Advances have been made using Tg strategies that allow investigators to reproduce features of these human disorders in mice. Tg mice with SOD1 mutations develop weakness and muscle atrophy associated with degenerative changes in motor neurons that result from the acquisition of toxic properties by mutant SOD1. The Tg mice that express mutant HuFAD-linked genes show behavioral impairments Aβ42 deposits associated with dystrophic neurites. It is found that the formation of Aβ42, derived by the aberrant processing of APP is influenced by APP mutations that increase the amount, length, and fibrillogenic properties of Aβ.

Metabolism and Function of Presenilin 1

Abstract: Neither the normal functions of presenilins nor the mechanism(s) by which familial Alzheimer’s disease (FAD)-linked mutations cause AD have been defined Presenilin 1 (PS1) is a polytopic membrane protein that is subject to endoproteolytic processing in vivo; PS1 derivatives accumulate to saturable levels and to ~ 1:1 stoichiometry by mechanism(s) that are not fully defined We show here that the two fragments coassemble Moreover, we have detected neither interactions between PS1/PS2 and amyloid precursor protein (APP) nor influences of presenilin expression on APP maturation/secretion To examine the in vivo function(s) of PS1, we developed mice with functionally inactivated PS1 alleles These animals die before birth and exhibit several developmental defects, including a poorly differentiated vertebral column, a phenotype traced to abnormal segmentation of somites Whole mount in situ hybridization analyses reveal that specification of somitic cell lineages is apparently unaffected, despite the clear disruption in somite segmentation However, notable differences in expression of Notch1 and Dll1 mRNAs were observed in PS −/− embryos; in contrast to wild-type embryos in which abundant expression of Notch1 and Dll1 mRNAs are observed in the presomitic mesoderm, the expression of these genes is nearly abolished in the PSl −/− embryos Hence, PS1 serves to regulate the spatiotemporal expression of Notch1 and Dll1 in the paraxial mesoderm Finally, we failed to detect any differences in the levels of Aβ42 and Aβ40 in brains of mice heterozygous for PS1 relative to wild-type litter mates Thus, mutations in PS1 probably cause AD not by the loss but rather by the gain of deleterious function of mutant polypeptides