Volume 7, Number 1, February 2005

Pages 1-2
Craig S. Atwood, Mark A. Smith, Richard L. Bowen (Handling Editor: James Geddes)
Letter to the Editor: Feedback on a Feedback Loop: The Hypothalamic-Pituitary-Gonadal Axis

Pages 3-13
Luisa Fasulo, Gabriele Ugolini, Antonino Cattaneo
Apoptotic effect of caspase-3 cleaved tau in hippocampal neurons and its potentiation by tau FTDP-mutation N279K
Abstract: Pathological changes in the microtubule associated protein tau are a major hallmark of many human dementias collectively defined as tauopathies. In familiar frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), several mutations in the tau gene have been identified showing that primary malfunction of tau can lead to neurodegeneration. In addition to mutation at genetic level, a number of post-translational modifications of tau occur in tauopathies, including abnormal phosphorylation and aberrant proteolysis described in Alzheimer’s Disease (AD). The presence of cleaved tau in AD neurons is associated with expression of markers for neuronal death. According to our previous work, tau is a substrate for the apoptotic protease caspase-3 that turns tau itself into an effector of apoptosis (tau cleaved at D-421), generating a positive-feedback loop that is self-propagating. Cleavage of tau by caspase-3 was recently confirmed to occur in AD brain as an early event. Here we show the apoptotic properties of tau fragment tau151-421 in primary cultures of rat hippocampal neurons; such cellular model is of special interest considering the selective vulnerability of hippocampal neurones in AD. The apoptotic capacity of tau151-421 is markedly enhanced by both treatment with amyloid peptide Aß25-35, and the FTDP-17 tau mutation N279K.

Pages 15-24
Maile R. Brown, Vimala Bondada, Jeffery N. Keller, Jeffery Thorpe, James W. Geddes
Proteasome or calpain inhibition does not alter cellular tau levels in neuroblastoma cells or primary neurons
Abstract: Impaired tau catabolism may contribute to tau accumulation and aggregation in Alzheimer’s disease and neurofibrillary tangle formation. This study examined the effects of proteasome and calpain inhibition on tau levels and turnover in primary rat hippocampal neurons and differentiated SH-SY5Y human neuroblastoma cells. Administration of proteasome (MG-115, lactacystin) or calpain (MDL28170) inhibitors for up to 24 hours did not alter tau levels in differentiated SH-SY5Y cells or rat hippocampal neurons. Addition of 1 μM and 10 μM MG-115 did not change total tau levels, but did result in increased reactivity of phosphorylation-dependent tau antibodies (PHF-1, CP-13) and decreased Tau-1 immunoreactivity. Administration of cycloheximide to inhibit de novo protein synthesis also did not alter tau levels in the presence or absence of lactacystin. These results demonstrate that although the proteasome and calpain protease systems are capable of degrading tau in cell-free assays, their inhibition does not alter cellular tau levels in primary neurons or differentiated neuroblastoma cells.

Pages 25-35
Shuang Chen, Natale T. Averett, Arlene Manelli, Mary Jo LaDu, Warren May, March D. Ard (Communicated by Yuan Luo)
Isoform-specific effects of apolipoprotein E on secretion of inflammatory mediators in adult rat microglia
Abstract: Inflammation mediated by activated microglia cells has been shown to contribute to the pathogenesis of Alzheimer disease (AD). Microglia are the immune cells in the central nervous system, and when activated they secrete the lipid-derived mediator prostaglandin E2 (PGE2), the cytokine interleukin-1β (IL-1β), and other inflammatory mediators. Apolipoprotein E isoform 4 (apoE4), coded for by the gene APOE4 (ε4), has been shown to correlate with higher risk of onset of AD, as well as with increased severity of other diseases with a neuroinflammatory component. This study investigated isoform-specific effects of apoE on the regulation of PGE2, COX2, and IL-1β expression. Two physiologically relevant preparations of apoE displayed an isoform-specific effect on inflammation in primary adult microglia cultured from adult rat brain cortex. Specifically, apoE4 alone, but not the more common isoform apoE3, stimulated secretion of PGE2 and IL-1β. The increase in PGE2 release stimulated by apoE4 was not accompanied by the upregulation of the COX-2 enzyme in microglia.

Pages 37-44
Ved Chauhan, Ashfaq M. Sheikh, Abha Chauhan, Warren D. Spivack, Michael D. Fenko, Mazhar N. Malik (Communicated by Ralph Martins)
Fibrillar amyloid beta-protein inhibits the activity of high molecular weight protease, and trypsin
Abstract: The effect of soluble amyloid beta-protein (sAβ) and fibrillar amyloid beta-protein (fAβ) on the casein-digesting activity of high molecular weight bovine brain protease (HMW protease) and trypsin was studied. While sAβ stimulated the casein-digesting activity of HMW protease in a concentration-dependent manner, it did not affect trypsin activity. Structure-activity relationship was studied by testing different soluble and fibrillar Aβ peptides. Various Aβ peptides affected casein-digesting activity of HMW protease differently: sAβ 1-40 > sAβ 22-35 = sAβ 1-11 = sAβ 1-16 > sAβ 1-28 = sAβ 31-35, while sAβ 12-28 and sAβ 25-35 had no effect. On the other hand, among the fibrillar Aβ peptides, only fAβ 1-40 significantly inhibited the casein-digesting activity of HMW protease. Tricine gel electrophoresis showed that sAβ was digested by trypsin while it remained un-cleaved in the presence of HMW protease. However, fAβ, a major component of amyloid plaques in Alzheimer’s disease, inhibited the casein-digesting activity of both HMW protease and trypsin. fAβ was found to be resistant to proteolysis by HMW protease and trypsin. The trypsin resistance starts in the early stage of fibrillization of Aβ, i.e., aggregated Aβ. Taken together, these results suggest that fibrillization of Aβ may affect the clearance of Aβ by inhibiting the brain proteases, thereby increasing the concentration of circulating Aβ, that may further increase the Aβ fibrillization.

Pages 45-61
Suzanne M. de la Monte and Jack R. Wands
Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer's disease
Abstract: Interest in characterizing the role of impaired insulin actions in Alzheimer’s disease (AD) and vascular dementia is growing exponentially. This review details what is currently known about insulin, insulin-like growth factor type I (IGF-I) and IGF-II proteins and their corresponding receptors in the brain, and delineates the major controversies pertaining to alterations in the expression and function of these molecules in AD. The various experimental animal models generated by over-expression, mutation, or depletion of genes that are critical to the insulin or IGF signaling cascades are summarized, noting the degrees to which they reproduce the histopathological, biochemical, molecular, or behavioral abnormalities associated with AD. Although no single model was determined to be truly representative of AD, depletion of the neuronal insulin receptor and intracerebroventricular injection of Streptozotocin reproduce a number of important aspects of AD-type neurodegeneration, and therefore provide supportive evidence that AD may be caused in part by neuronal insulin resistance, i.e. brain diabetes. The extant literature did not resolve whether the CNS insulin resistance in AD represents a local disease process, or complication/extension of peripheral insulin resistance, i.e. chronic hyperglycemia, hyperinsulinemia, and Type 2 diabetes mellitus. The available epidemiological data are largely inconclusive with regard to the contribution of Type 2 diabetes mellitus to cognitive impairment and AD-type neurodegeneration. A major conclusion drawn from this review is that there is a genuine need for thorough and comprehensive study of the neuropathological changes associated with diabetes mellitus, in the presence or absence of superimposed AD or vascular dementia. Strategies for intervention may depend entirely upon whether the CNS disease processes are mediated by peripheral, central, or both types of insulin resistance.

Pages 63-80
Eric Steen, Benjamin M. Terry, Enrique J. Rivera, Jennifer L. Cannon, Thomas R. Neely, Rose Tavares, X. Julia Xu, Jack R. Wands, Suzanne M. de la Monte
Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease---is this type 3 diabetes?
Abstract: The neurodegeneration that occurs in sporadic Alzheimer’s disease (AD) is consistently associated with a number of characteristic histopathological, molecular, and biochemical abnormalities, including cell loss, abundant neurofibrillary tangles and dystrophic neurites, amyloid-β deposits, increased activation of pro-death genes and signaling pathways, impaired energy metabolism/mitochondrial function, and evidence of chronic oxidative stress. The general inability to convincingly link these phenomena has resulted in the emergence and propagation of various heavily debated theories that focus on the role of one particular element in the pathogenesis of all other abnormalities. However, the accumulating evidence that reduced glucose utilization and deficient energy metabolism occur early in the course of disease, suggests a role for impaired insulin signaling in the pathogenesis of AD. The present work demonstrates extensive abnormalities in insulin and insulin-like growth factor, types I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system (CNS) neurons, the expression levels are markedly reduced in AD. These abnormalities were associated with reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA, IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt (activated), and increased glycogen synthase kinase-3β activity and amyloid precursor protein mRNA expression. The strikingly reduced CNS expression of genes encoding insulin, IGF-I, and IGF-II, as well as the insulin and IGF-I receptors, suggests that AD may represent a neuro-endocrine disorder that resembles, yet is distinct from diabetes mellitus. Therefore, we propose the term, “Type 3 Diabetes” to reflect this newly identified pathogenic mechanism of neurodegeneration.

Commentary on the Steen et al. manuscript:

    Pages 81-84
    Xiongwei Zhu, George Perry, Mark A. Smith
    Insulin signaling, diabetes mellitus and risk of Alzheimer disease

Pages 85-91
Transcript: Alzheimer Research Forum Live Discussion
Alzheimer's: A Triple Whammy. Why Are So Many Neurodegenerative Diseases Single, Double, or Triple Amyloidoses?

Page 93
Book Review: 100 Questions & Answers About Alzheimer's Disease, by Thomas M. Wisniewski and Marcin Sadowski, Jones & Bartlett Publishers, Inc., May 2004, 214 pp. Reviewed by Catarina Oliveira.

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