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The article discusses the different factors and protein abnormalities that have been found to be responsible for the onset of Alzheimer's disease, a deterioration of memory and other cognitive domains leading to death within three to five years after diagnosis. Some of the different treatment methodologies for the disease are highlighted.

A 41-year-old man was admitted to a hospital because of weakness in his legs and difficulty walking. A chest X-ray showed lymph node enlargement and he also had difficulty urinating. An MRI scan showed no abnormalities in his spinal column, but analysis of cerebrospinal fluid indicated that he might have sarcoidosis. This disease can affect any organ but is most common in the lungs. A biopsy of his lung confirmed that he had sarcoidosis. Sarcoidosis in the spine is very unusual.

A23187 calcium region increases the formation of amyloid beta peptide (A-beta) during metabolism in cultured cells. A-beta formation depends on the extracellular protein of the intact cells and is independent of CAMP and C-dependent protein kinase pathway. Calcium formation influences the phosphorylation and development of beta amyloid precursor protein (beta-APP). Defective calcium metabolism causes neurodegenerative diseases such as Alzheimer's disease.

Abstract Background A recent development in non-invasive techniques to predict intracranial pressure (ICP) termed venous ophthalmodynamometry (vODM) has made measurements in absolute units possible. However, there has been little progress to show utility in the clinic or field. One important application would be to predict changes in actual ICP during adaptive responses to physiologic stress such as hypoxia. A causal relationship between raised intracranial pressure and acute mountain sickness (AMS) is suspected. Several MRI studies report that modest physiologic increases in cerebral volume, from swelling, normally accompany subacute ascent to simulated high altitudes. Objectives 1) Validate and calibrate an advanced, portable vODM instrument on intensive patients with raised intracranial pressure and 2) make pilot, non-invasive ICP estimations of normal subjects at increasing altitudes. Methods The vODM was calibrated against actual ICP in 12 neurosurgical patients, most affected with acute hydrocephalus and monitored using ventriculostomy/pressure transducers. The operator was blinded to the transducer read-out. A clinical field test was then conducted on a variable data set of 42 volunteer trekkers and climbers scaling Mt. Everest, Nepal. Mean ICPs were estimated at several altitudes on the ascent both across and within subjects. Results Portable vODM measurements increased directly and linearly with ICP resulting in good predictability (r = 0.85). We also found that estimated ICP increases normally with altitude (10 ± 3 mm Hg; sea level to 20 ± 2 mm Hg; 6553 m) and that AMS symptoms did not correlate with raised ICP. Conclusion vODM technology has potential to reliably estimate absolute ICP and is portable. Physiologic increases in ICP and mild-mod AMS are separate responses to high altitude, possibly reflecting swelling and vasoactive instability, respectively.

Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer's disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples. In two rodent AD models, mTORC1 and C2 activities were also decreased. In a neuronal culture model of AD characterized by accumulation of cellular amyloid-β (Aβ)42, mTORC1 activity was reduced. Autophagic vesicles and markers were correspondingly increased and new protein synthesis was inhibited, consistent with mTORC1 hypofunction. Interestingly, mTORC2 activity in neural culture seemed resistant to the effects of intracellular amyloid. In various cell lines, Aβ expression provoked insulin resistance, characterized by inhibition of stimulated Akt phosphorylation, and an increase in negative mTORC1 regular, p-AMPK, itself a nutrient sensor. Rapamycin decreased phospho-mTOR and to lesser degree p-Rictor. This further suppression of mTORC1 activity protected cells from Aβ-induced toxicity and insulin resistance. More striking, Rictor over-expression fully reversed the Aβ-effects on primary neuronal cultures. Finally, using in vitro assay, Rictor protein addition completely overcame oligomeric Aβ-induced inhibition of the PDK-Akt activation step. We conclude that striking a new balance by restoring mTORC2 abundance and/or inhibition of mTORC1 has therapeutic potential in AD. [ABSTRACT FROM AUTHOR]

Neurodegeneration in Alzheimer’s disease (AD) has been linked to intracellular accumulation of misfolded proteins and dysregulation of intracellular Ca2+. In the current work, we determined the contribution of specific Ca2+ pathways to an alteration in Ca2+ homeostasis in primary cortical neurons from an adult triple transgenic (3xTg-AD) mouse model of AD that exhibits intraneuronal accumulation of β-amyloid proteins. Resting free Ca2+ concentration ([Ca2+]i), as measured with Ca2+-selective microelectrodes, was greatly elevated in neurons from 3xTg-AD and APPSWE mouse strains when compared with their respective non-transgenic neurons, while there was no alteration in the resting membrane potential. In the absence of the extracellular Ca2+, the [Ca2+]i returned to near normal levels in 3xTg-AD neurons, demonstrating that extracellular Ca2+contributed to elevated [Ca2+]i. Application of nifedipine, or a non-L-type channel blocker, SKF-96365, partially reduced [Ca2+]i. Blocking the ryanodine receptors, with ryanodine or FLA-365 had no effect, suggesting that these channels do not contribute to the elevated [Ca2+]i. Conversely, inhibition of inositol trisphosphate receptors with xestospongin C produced a partial reduction in [Ca2+]i. These results demonstrate that an elevation in resting [Ca2+]i, contributed by aberrant Ca2+entry and release pathways, should be considered a major component of the abnormal Ca2+ homeostasis associated with AD. [ABSTRACT FROM AUTHOR]

Early events in Alzheimer's disease (AD) pathogenesis implicate the accumulation of ß-amyloid (Aß) peptide inside neurons in vulnerable brain regions. However, little is known about the consequences of intraneuronal Aß on signaling mechanisms. Here, we demonstrate, using an inducible viral vector system to drive intracellular expression of Aß42 peptide in primary neuronal cultures, that this accumulation results in the inhibition of the Akt survival signaling pathway. Induction of intraneuronal Aß42 expression leads to a sequential decrease in levels of phospho-Akt, increase in activation of glycogen synthase kinase-3ß, and apoptosis. Downregulation of Akt also paralleled intracellular Aß accumulation in vivo in the Tg2576 AD mouse model. Overexpression of constitutively active Akt reversed the toxic effects of Aß through a mechanism involving the induction of heat shock proteins (Hsps). We used a small-interfering RNA approach to explore the possibility of a link between Akt activity and Hsp70 expression and concluded that neuroprotection by Akt could be mediated through downstream induction of Hsp70 expression. These results suggest that the early dysfunction associated with intraneuronal Aß accumulation in AD involve the associated impairments of Akt signaling and suppression of the stress response. [ABSTRACT FROM AUTHOR]

Intracellular β-amyloid 42 (Aβ42) accumulation is increasingly recognized as an early event in the pathogenesis of Alzheimer's disease (AD). We have developed a doxycycline-inducible adenoviral-based system that directs intracellular Aβ42 expression and accumulation into the endoplasmic reticulum of primary neuronal cultures in a regulated manner. Aβ42 exhibited a perinuclear distribution in cell bodies and an association with vesicular compartments. Virally expressed intracellular Aβ42 was toxic to neuronal cultures 24 hr after induction in a dose-dependent manner. Aβ42 expression prompted the rapid induction of stress-inducible Hsp70 protein in neurons, and virally mediated Hsp70 overexpression rescued neurons from the toxic effects of intracellular Aβ accumulation. Together, these results implicate the cellular stress response as a possible modulator of Aβ-induced toxicity in neuronal cultures. [ABSTRACT FROM AUTHOR]

The article presents a study which examined how the transgenic expression of β-APP in fast-twitch skeletal muscle leads to calcium dyshomeostasis and inclusion body myositis (IBM)-like pathology. A recognized pathological feature of human IBM is the intracellular deposition of the β-amyloid peptide in skeletal muscle fibers. Transgene integration was analyzed in total DNA extracted from distal tail samples through genomic Southern blot hybridizations and polymerase chain reaction.

Abstract: Inclusion body myositis (IBM), the most common muscle disorder in the elderly, is partly characterized by dysregulation of β-amyloid precursor protein (βAPP) expression and abnormal, intracellular accumulation of full-length βAPP and β-amyloid epitopes. The present study examined the effects of β-amyloid accumulation on force generation and Ca2+ release in skeletal muscle from transgenic mice harboring human βAPP and assessed the consequence of Aβ1–42 modulation of the ryanodine receptor Ca2+ release channels (RyRs). β-Amyloid laden muscle produced less peak force and exhibited Ca2+ transients with smaller amplitude. To determine whether modification of RyRs by β-amyloid underlie the effects observed in muscle, in vitro Ca2+ release assays and RyR reconstituted in planar lipid bilayer experiments were conducted in the presence of Aβ1–42. Application of Aβ1–42 to RyRs in bilayers resulted in an increased channel open probability and changes in gating kinetics, while addition of Aβ1–42 to the rabbit SR vesicles resulted in RyR-mediated Ca2+ release. These data may relate altered βAPP metabolism in IBM to reductions in RyR-mediated Ca2+ release and muscle contractility. [ABSTRACT FROM AUTHOR]

The relative scarcity of inclusion-affected muscle cells or markers of cell death in inclusion body myositis (IBM) is in distinction to the specific and early intracellular deposition of several Alzheimer's Disease (AD)-related proteins. The current study examined the possible correlation between myotube β-amyloid and/or Tau accumulations and a widespread mishandling of intracellular muscle calcium concentration that could potentially account for the unrelenting weakness in affected patients. Cultured myogenic cells (C2C12) expressed β-amyloid-42 (Aβ42) and fetal Tau peptides, as human transgenes encoded by herpes simplex virus, either individually or concurrently. Co-expression of Aβ42 in C2C12 myotubes resulted in hyperphosphorylation of Tau protein that was not observed when Tau was expressed alone. Resting calcium concentration and agonist-induced RyR-mediated Ca2+ release were examined using calcium-specific microelectrodes and FLuo-4 epifluorescence, respectively. Co-expression of Aβ42 and Tau cooperatively elevated basal levels of myoplasmic-free calcium, an effect that was accompanied by depolarization of the plasma membrane. Sareoplasmic reticulum (SR) calcium release, induced by KCl depolarization, was not affected by Aβ42 or Tau. In contrast, expression of Aβ42, Tau, or Aβ42 together with Tau resulted in enhanced sensitivity of ryanodine receptors to activation by caffeine. Notably, expression of β-amyloid, alone, was sufficient to result in an increased sensitivity to direct activation by caffeine. Current results indicate that amyloid proteins cooperate to raise resting calcium levels and that these effects are associated with a passive SR Ca2+ leak and Tau hyperphosphorylation in skeletal muscle. [ABSTRACT FROM AUTHOR]

The significance of intracellular beta-amyloid (Abeta(42)) accumulation is increasingly recognized in Alzheimer's disease (AD) pathogenesis. Abeta removal mechanisms that have attracted attention include IDE/neprilysin degradation and antibody-mediated uptake by immune cells. However, the role of the ubiquitin-proteasome system (UPS) in the disposal of cellular Abeta has not been fully explored. The E3 ubiquitin ligase Parkin targets several proteins for UPS degradation, and Parkin mutations are the major cause of autosomal recessive Parkinson's disease. We tested whether Parkin has cross-function to target misfolded proteins in AD for proteasome-dependent clearance in SH-SY5Y and primary neuronal cells. Wild-type Parkin greatly decreased steady-state levels of intracellular Abeta(42), an action abrogated by proteasome inhibitors. Intracellular Abeta(42) accumulation decreased cell viability and proteasome activity. Accordingly, Parkin reversed both effects. Changes in mitochondrial ATP production from Abeta or Parkin did not account for their effects on the proteasome. Parkin knock-down led to accumulation of Abeta. In AD brain, Parkin was found to interact with Abeta and its levels were reduced. Thus, Parkin is cytoprotective, partially by increasing the removal of cellular Abeta through a proteasome-dependent pathway.

Intraneuronal beta-amyloid (Abeta(i)) accumulates early in Alzheimer's disease (AD) and inclusion body myositis. Several organelles, receptor molecules, homeostatic processes, and signal transduction components have been identified as sensitive to Abeta. Although prior studies implicate the insulin-PI3K-Akt signaling cascade, a specific step within this or any essential metabolic or survival pathway has not emerged as a molecular target. We tested the effect of Abeta42 on each component of this cascade. In AD brain, the association between PDK and Akt, phospho-Akt levels and its activity were all decreased relative to control. In cell culture, Abeta(i) expression inhibited both insulin-induced Akt phosphorylation and activity. In vitro experiments identified that beta-amyloid (Abeta), especially oligomer preparations, specifically interrupted the PDK-dependent activation of Akt. Abeta(i) also blocked the association between PDK and Akt in cell-based and in vitro experiments. Importantly, Abeta did not interrupt Akt or PI3K activities (once stimulated) nor did it affect more proximal signal events. These results offer a novel therapeutic strategy to neutralize Abeta-induced energy failure and neuronal death.

The C-terminus Hsp70 interacting protein (CHIP) has dual function as both co-chaperone and ubiquitin ligase. CHIP is increasingly implicated in the biology of polyglutamine expansion disorders, Parkinson's disease and tau protein in Alzheimer's disease. We investigated the involvement of CHIP in the metabolism of the beta-amyloid precursor protein and its derivative beta-amyloid (Abeta). Using immunoprecipitation, fluorescence localization and crosslinking methods, endogenous CHIP and betaAPP interact in brain and cultured skeletal myotubes as well as when they are expressed in stable HEK cell lines. Their interaction is confined to Golgi and ER compartments. In the presence of the proteasome inhibitor with MG132, endogenous and expressed betaAPP levels are significantly increased and accordingly, the interaction with CHIP enhanced. Concurrently, levels of Hsp70 were most consistently induced by proteasome inhibition among the various heat shock proteins (HSPs) tested. Thus, complexes of CHIP, Hsp70 and holo-betaAPP (as well as C-terminal fragments) were stabilized by the action of MG132. Moreover, CHIP itself is shown to both increase cellular holo-betaAPP levels and protect it from oxidative stress and degradation. Interestingly, CHIP also promotes the association of ubiquitin with betaAPP, implying that a smaller pool of betaAPP is destined for proteasomal processing. In neuronal cultures, CHIP and Hsp70/90 expression reduce steady-state cellular Abeta levels and hasten its degradation in pulse-chase experiments. The functional significance of CHIP and HSP interactions, especially with Hsp70, was tested using siRNA and in neuronal cells where protection from Abeta-induced toxicity is shown. We conclude that CHIP, as a bimolecular switch, interacts with HSP to stabilize normal holo-betaAPP on the one hand while also assisting in the ubiquitination of a subpopulation of betaAPP molecules that are destined for proteasome degradation. CHIP also hastens the clearance of Abeta in a manner consistent with its known neuroprotective properties.

Intracellular deposition of the beta-amyloid (Abeta) peptide is an increasingly recognized pathological hallmark associated with neurodegeneration and muscle wasting in Alzheimer's disease (AD) and inclusion body myositis (IBM), respectively. Previous reports have implicated dysregulation of beta-amyloid precursor protein (betaAPP) expression in IBM. Accumulation of full-length betaAPP, its various proteolytic derivatives including Abeta, and phospho-tau into vacuolated inclusions is an early pathogenic event. We previously reported on a statistical tendency favoring fast twitch fiber involvement in IBM, reminiscent of the tissue specific patterns of misfolded protein deposition seen in neurodegenerative diseases. To test this principle, we generated an animal model in which human wild-type (WT) betaAPP expression was limited to postnatal type II skeletal muscle. Hemizygous transgenic mice harboring increased levels of holo betaAPP751 and Abeta in skeletal muscle fibers became significantly weaker with age compared with nontransgenic littermates and exhibited typical myopathic features. A subpopulation of dissociated muscle fibers from transgenic mice exhibited a 2-fold increase in resting calcium and membrane depolarization compared with nontransgenic littermates. Taken together, these data indicate that overexpression of human betaAPP in fast twitch skeletal muscle of transgenic mice is sufficient for the development of some features characteristic of IBM, including abnormal tau histochemistry. The increase in resting calcium and depolarization are novel findings, suggesting both a mechanism for the weakness and an avenue for therapeutic intervention in IBM.

Early events in Alzheimer's disease (AD) pathogenesis implicate the accumulation of beta-amyloid (Abeta) peptide inside neurons in vulnerable brain regions. However, little is known about the consequences of intraneuronal Abeta on signaling mechanisms. Here, we demonstrate, using an inducible viral vector system to drive intracellular expression of Abeta42 peptide in primary neuronal cultures, that this accumulation results in the inhibition of the Akt survival signaling pathway. Induction of intraneuronal Abeta42 expression leads to a sequential decrease in levels of phospho-Akt, increase in activation of glycogen synthase kinase-3beta, and apoptosis. Downregulation of Akt also paralleled intracellular Abeta accumulation in vivo in the Tg2576 AD mouse model. Overexpression of constitutively active Akt reversed the toxic effects of Abeta through a mechanism involving the induction of heat shock proteins (Hsps). We used a small-interfering RNA approach to explore the possibility of a link between Akt activity and Hsp70 expression and concluded that neuroprotection by Akt could be mediated through downstream induction of Hsp70 expression. These results suggest that the early dysfunction associated with intraneuronal Abeta accumulation in AD involve the associated impairments of Akt signaling and suppression of the stress response.

Intracellular beta-amyloid 42 (Abeta42) accumulation is increasingly recognized as an early event in the pathogenesis of Alzheimer's disease (AD). We have developed a doxycycline-inducible adenoviral-based system that directs intracellular Abeta42 expression and accumulation into the endoplasmic reticulum of primary neuronal cultures in a regulated manner. Abeta42 exhibited a perinuclear distribution in cell bodies and an association with vesicular compartments. Virally expressed intracellular Abeta42 was toxic to neuronal cultures 24 hr after induction in a dose-dependent manner. Abeta42 expression prompted the rapid induction of stress-inducible Hsp70 protein in neurons, and virally mediated Hsp70 overexpression rescued neurons from the toxic effects of intracellular Abeta accumulation. Together, these results implicate the cellular stress response as a possible modulator of Abeta-induced toxicity in neuronal cultures.