Muscle atrophy occurs in many pathological states and results primarily from accelerated protein degradation and activation of the ubiquitin-proteasome pathway. However, the importance of lysosomes in muscle atrophy has received little attention. Activation of FoxO transcription factors is essential for the atrophy induced by denervation or fasting, and activated FoxO3 by itself causes marked atrophy of muscles and myotubes. Here, we report that FoxO3 does so by stimulating overall protein degradation and coordinately activating both lysosomal and proteasomal pathways. Surprisingly, in C2C12 myotubes, most of this increased proteolysis is mediated by lysosomes. Activated FoxO3 stimulates lysosomal proteolysis in muscle (and other cell types) by activating autophagy. FoxO3 also induces the expression of many autophagy-related genes, which are induced similarly in mouse muscles atrophying due to denervation or fasting. These studies indicate that decreased IGF-1-PI3K-Akt signaling activates autophagy not only through mTOR but also more slowly by a transcription-dependent mechanism involving FoxO3.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects more than 15 million people worldwide. Within the next generation, these numbers will more than double. To assist in the elucidation of pathogenic mechanisms of AD and related disorders, such as frontotemporal dementia , genetically modified mice, flies, fish and worms were developed, which reproduce aspects of the human histopathology, such as b-amyloidcontaining plaques and tau-containing neurofibrillary tangles (NFT). In mice, the tau pathology caused selective behavioral impairment, depending on the distribution of the tau aggregates in the brain. b-Amyloid induced an increase in the numbers of NFT, whereas the opposite was not observed in mice. In b-amyloid-producing transgenic mice, memory impairment was associated with increased levels of b-amyloid. Active and passive b-amyloid-directed immunization caused the removal of b-amyloid plaques and restored memory functions. These findings have since been translated to human therapy. This review aims to discuss the suitability and limitations of the various animal models and their contribution to an understanding of the pathophysiology of AD and related disorders. Keywords: Alzheimer's disease; frontotemporal dementia; b-amyloid; tau; transgenic; C. elegans; Drosophila; sea lamprey; mice; behavior; memory; therapy; immunization Alzheimer's disease and related disorders: neuropathology, genetics and clinical featuresIn 1907, the two key histopathological hallmarks of Alzheimer's disease (AD), b-amyloid plaques and neurofibrillary tangles (NFT), were for the first time described by Alois Alzheimer when he examined brain sections of his patient Auguste D. 1 Since then, the number of PubMed entries for 'Alzheimer' steadily increased and, in 2002 alone, added up to 5213 entries. The last 20 years of AD research, with the help of animal models, assisted in the elucidation of aspects of the pathophysiology of AD and the relationship of the two major lesions. Parallel to this increased insight into disease mechanisms, the number of AD patients is rising as the numbers of old people are increasing in many countries. Moreover, the incidence of AD rises from less than 2% for people under the age of 60 to about 30% in people older than 85. 2 b-Amyloid plaques and Ab processing b-Amyloid plaques are one of the histopathological hallmarks of AD. The term amyloid has been introduced to describe a heterogeneous class of protein aggregates with a b-pleated sheet secondary structure, which confers affinity to the histochemical dye congo red. In AD, b-amyloid is deposited around meningeal and cerebral vessels, and in the gray matter as b-amyloid plaques. The major proteinaceous component is a 40-42 amino-acid polypeptide termed Ab (Ab 40 and Ab 42 ), which is derived by proteolysis from the amyloid precursor protein (APP). 3,4 APP can be proteolytically cleaved by the membrane-associated a-secretase, which cleaves APP within the Ab domain and secretes the aminoterminal portion of APP (APP s ). This p...

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Many proteins that are implicated in human disease are posttranslationally modified. This includes the microtubule-associated protein tau that is deposited in a hyperphosphorylated form in brains of Alzheimer's disease patients. The focus of this review article is on the physiological and pathological phosphorylation of tau; the relevance of aberrant phosphorylation for disease; the role of kinases and phosphatases in this process; its modeling in transgenic mice, flies, and worms; and implications of phosphorylation for therapeutic intervention.

Of all forms of dementia, Alzheimer's disease is the most prevalent. It is histopathologically characterized by beta-amyloid-containing plaques, tau-containing neurofibrillary tangles, reduced synaptic density and neuronal loss in selected brain areas. For the rare familial forms of Alzheimer's disease, pathogenic mutations have been identified in both the gene encoding the precursor of the Abeta peptide, APP, itself and in the presenilin genes which encode part of the APP-protease complex. For the more frequent sporadic forms of Alzheimer's disease, the pathogenic trigger has not been unambiguously identified. Whether Abeta is again the main cause remains to be heavily discussed. In a related disorder termed frontotemporal dementia, which is characterized by tangles in the absence of beta-amyloid deposition, mutations have been identified in tau which also lead to neurodegeneration and dementia. For Alzheimer's disease the existence of familial forms lead to the proposition of the amyloid cascade hypothesis, which claims that beta-amyloid causes or enhances the tangle pathology. In this review, we describe tau transgenic mouse models in which aspects of the tau-associated pathology, including tangle formation, has been achieved. Moreover, tau transgenic mouse and tissue-culture models were used to test the amyloid cascade hypothesis. In addition, we discuss alternative hypotheses to explain the sporadic forms. The animal and tissue-culture models will provide insight into the underlying biochemical mechanisms of tau aggregation and nerve cell degeneration. These mechanisms may be partially shared between sporadic Alzheimer's disease, the familial forms and frontotemporal dementia. Eventually, Alzheimer's disease may be redefined based on biochemical events rather than phenotype.

Protein phosphatase (PP2A) 2A is a hetero-trimeric holoenzyme that consists of a core dimer composed of a catalytic subunit that is tightly complexed with the scaffolding subunit PR65/A. This core dimer associates with variable regulatory subunits of the PR55/B, PR61/B', PR72/B" and PR93/PR110/B"' families. As PP2A holoenzymes containing PR55/B have been shown to be involved in the pathogenesis of Alzheimer's disease, we characterized the PR55/B family with particular emphasis on its distribution and expression in the brain. We determined the genomic organization of all members of the PR55/B family and cloned their murine cDNAs. Thereby, two novel splice variants of PR55/Bbeta were identified. In addition, Northern blot analysis revealed multiple transcripts for the different PR55 subunits, suggesting a higher variability within the PR55 family. In situ hybridization analysis revealed that all PR55/B subunits were widely expressed in the brain. PR55/Balpha and Bbeta protein expression varies significantly in areas of the brain affected by neurodegenerative diseases such as the hippocampus or cerebellum. At the cellular level, PR55/Bbeta protein expression was confined to neurons, whereas PR55/Balpha was also expressed in activated astrocytes indicating that the PR55 isoforms confer a different function to the holoenzyme complex. As PP2A dysfunction has been demonstrated to contribute to various human diseases, dissecting the PP2A holoenzyme and its particular function in different cell types will assist in the development of novel therapeutic strategies.

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