Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Alzheimer's Disease: Genes, Proteins, and Therapy

Studies of the molecular basis of Alzheimer's disease exemplify the increasingly blurred distinction between basic and applied biomedical research.The four genes so far implicated in familial Alzheimer's disease have each been shown to elevate brain levels of the self-aggregating amyloid-β protein, leading gradually to profound neuronal and glial alteration, synaptic loss and dementia. Progress in understanding this cascade has helped to identify specific therapeutic targets and provides a model for elucidating other neurodegenerative disorders.

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Translating cell biology into therapeutic advances in Alzheimer's disease

Alzheimer’s disease (AD) was first described a little more than 100 years ago. It is the most common cause of dementia with an estimated prevalence of 30 million people worldwide, a number that is expected to quadruple in 40 years. There currently is no effective treatment that delays the onset or slows the progression of AD. However, major scientific advances in the areas of genetics, biochemistry, cell biology, and neuroscience over the past 25 years have changed the way we think about AD. This review discusses some of the challenges to translating these basic molecular and cellular discoveries into clinical therapies. Current information suggests that if the disease is detected before the onset of overt symptoms, it is possible that treatments based on knowledge of underlying pathogenesis can and will be effective.

Alzheimer’s Disease: The Challenge of the Second Century

The cell biology of β-amyloid precursor protein and presenilin in Alzheimer's disease

Intensive studies of three proteins--Presenilin, Notch, and the amyloid precursor protein (APP)--have led to the recognition of a direct intersection between early development and late-life neurodegeneration. Notch signaling mediates many different intercellular communication events that are essential for determining the fates of neural and nonneural cells during development and in the adult. The Notch receptor acts in a core pathway as a membrane-bound transcription factor that is released to the nucleus by a two-step cleavage mechanism called regulated intramembrane proteolysis (RIP). The second cleavage is effected by Presenilin, an unusual polytopic aspartyl protease that apparently cleaves Notch and numerous other single-transmembrane substrates within the lipid bilayer. Another Presenilin substrate, APP, releases the amyloid ss-protein that can accumulate over time in limbic and association cortices and help initiate Alzheimer's disease. Elucidating the detailed mechanism of Presenilin processing of membrane proteins is important for understanding diverse signal transduction pathways and potentially for treating and preventing Alzheimer's disease.

NOTCH AND PRESENILIN: Regulated Intramembrane Proteolysis Links Development and Degeneration

Mutant Human Presenilin 1 Protects presenilin 1 Null Mouse against Embryonic Lethality and Elevates Aβ1–42/43 Expression

We report the characterization of Gsh-1, a novel murine homeobox gene. Northern blot analysis revealed a transcript of approximately 2 kb in size present at embryonic days 10.5, 11.5, and 12.5 of development. The cDNA sequence encoded a proline rich motif, a polyalanine tract, and a homeodomain with strong homology to those encoded by the clustered Hox genes. The Gsh-1 expression pattern was determined for days E8.5 to E13.5 by whole mount and serial section in situ hybridizations. Gsh-1 transcription was restricted to the central nervous system. Expression is present in the neural tube and hindbrain as two continuous, bilaterally symmetrical stripes within neural epithelial tissue. In the mesencephalon, expression is seen as a band across the most anterior portion. There is also diencephalon expression in the anlagen of the thalamus and the hypothalamus as well as in the optic stalk, optic recess, and the ganglionic eminence. Moreover, through the use of fusion proteins containing the Gsh-1 homeodomain, we have determined the consensus DNA ninding site of the Gsh-1 homeoprotein to be GCT/CA/CATTAG/A. ©1995 Wiley-Liss, Inc.

Gsh-1: a novel murine homeobox gene expressed in the central nervous system

The genes encoding the melanocortin-3 receptor and melanocortin-5 receptor have been cloned from rhesus monkey. Heterologous expression in CHO cells indicated species dependent in vitro pharmacological properties for the human and rhesus melanocortin-5 receptors. Several peptides including NDP-alpha-MSH, alpha-MSH, MT-II and ACTH1-24 are more potent at the rhesus melanocortin-5 receptor than the human melanocortin-5 receptor by more than 10-fold. In contrast, we found no species difference in pharmacological properties between the human and rhesus melanocortin-3 receptors. Such a species-dependent pharmacological difference for melanocortin-5 receptor appears to be an exception compared to other G protein-coupled receptors from human and rhesus monkey.

Species-dependent pharmacological properties of the melanocortin-5 receptor.

Theβ-amyloid peptide (Aβ), the major component of the neuritic plaques characterizing Alzheimer’s disease (AD), is a 39 to 43 amino acid peptide derived from proteolytic cleavage of a larger β-amyloid precursor protein (APP). Mutations in the APP gene have been identified which cause familial, early onset AD, suggesting that APP metabolism is a central event in AD progression (Mullan & Crawford, 1993). APP is an abundant protein in the brain and Aβ is produced not only in AD patients, but also in cerebrospinal fluid (CSF) of normal individuals (Selkoe, 1994). APP has been implicated in numerous activities based on in vitro studies, such as regulation of cell adhesion, neurite outgrowth and intraneuronal calcium (Selkoe, 1994). However, the in vivo function of APP remains unclear.

Gurparkash Singh

Papers

Mutant Human Presenilin 1 Protects presenilin 1 Null Mouse against Embryonic Lethality and Elevates Aβ1–42/43 Expression

Gsh-1: a novel murine homeobox gene expressed in the central nervous system

Species-dependent pharmacological properties of the melanocortin-5 receptor.

APP Knockout and APP Over-Expression in Transgenic Mice

Transgenes tier welches eine familiäre form vom menschlichen amyloiden vorläuferprotein exprimiert