Alzheimer's Disease and Its Possible Evolutionary Origin: Hypothesis.

The enormous, 2-3-million-year evolutionary expansion of hominin neocortices to the current enormity enabled humans to take over the planet. However, there appears to have been a glitch, and it occurred without a compensatory expansion of the entorhinal cortical (EC) gateway to the hippocampal memory-encoding system needed to manage the processing of the increasing volume of neocortical data converging on it. The resulting age-dependent connectopathic glitch was unnoticed by the early short-lived populations. It has now surfaced as Alzheimer's disease (AD) in today's long-lived populations. With advancing age, processing of the converging neocortical data by the neurons of the relatively small lateral entorhinal cortex (LEC) inflicts persistent strain and high energy costs on these cells. This may result in their hyper-release of harmless Aß1-42 monomers into the interstitial fluid, where they seed the formation of toxic amyloid-ß oligomers (AßOs) that initiate AD. At the core of connectopathic AD are the postsynaptic cellular prion protein (PrPC). Electrostatic binding of the negatively charged AßOs to the positively charged N-terminus of PrPC induces hyperphosphorylation of tau that destroys synapses. The spread of these accumulating AßOs from ground zero is supported by Aß's own production mediated by target cells' Ca2+-sensing receptors (CaSRs). These data suggest that an early administration of a strongly positively charged, AßOs-interacting peptide or protein, plus an inhibitor of CaSR, might be an effective AD-arresting therapeutic combination.

Targeting Human Astrocytes' Calcium-sensing Receptors for Treatment of Alzheimer's Disease.

Understanding the pathophysiology of Alzheimer's disease (AD) in the principal human neural cells is necessary for finding therapeutics for this illness. To help do this, we have been using freshly cultured functionally normal cerebral cortical adult human astrocytes (NAHAs) and postnatal neurons. The findings show that amyloid-ß oligomers (Aß-os) binding to calcium-sensing receptors (CaSRs) on NAHAs and neuron surfaces trigger signals capable of driving AD pathogenesis. This Aß•CaSR signalling shifts the amyloid precursor protein (APP) from its α-secretase shedding producing neurotrophic/neuroprotective soluble (s)APPα to its ß-secretase cleaving engendering AD-driving Aß42/Aß42-os peptides. Aß•CaSR signalling in NAHAs also drives the release of toxic hyper-phosphorylated Tau proteins in exosomes, and of nitric oxide, and VEGF-A. These several harmful agents comprise the neuron-killing machinery, driving the very slowly spreading AD neurocontagion. VEGF-A over-secretion from Aß-exposed blood vessel-attached astrocytes induces a functional magnetic resonance imaging- detectable hippocampal neoangiogenesis which indicates approaching AD in amnestic minor cognitive impairment (aMCI) patients. Most important in AD's regard, selective allosteric CaSR antagonists (calcylitics) added to Aß42/Aß42-os-exposed NAHAs (or to human neuron cultures) rescue the extracellular shedding of neurotrophic/ neuroprotective sAPPα and suppress all the neurotoxic effects of Aß•CaSR signalling even when multiple microglial cytokines are also present. Therefore, since the multipotent calcilytics would be reasonably safe and inexpensive drugs for humans, it is worthwhile testing them as AD therapeutics in clinical trials especially in persons in the earliest detectable stages of AD neuropathology progression such as aMCI.

The Possible Roles of the Dentate Granule Cell's Leptin and Other Ciliary Receptors in Alzheimer's Neuropathology.

Dentate-gyral granule cells in the hippocampus plus dentate gyrus memory-recording/retrieving machine, unlike most other neurons in the brain, are continuously being generated in the adult brain with the important task of separating overlapping patterns of data streaming in from the outside world via the entorhinal cortex. This "adult neurogenesis" is driven by tools in the mature granule cell's cilium. Here we report our discovery of leptin's LepRb receptor in this cilium. In addition, we discuss how ciliary LepRb signaling might be involved with ciliary p75NTR and SSTR3 receptors in adult neurogenesis and memory formation as well as attenuation of Alzheimer's neuropathology by reducing the production of its toxic amyloid-ß-derived drivers.

Preventing the spread of Alzheimer's disease neuropathology: a role for calcilytics?

The "amyloid cascade hypothesis" posits that an extracellular build-up of amyloid-ß oligomers (Aß-os) and polymers (fibrils) subsequently inducing toxic hyperphosphorylated (p)-Tau oligomers (p-Tau-os) and neurofibrillary tangles starts the sporadic late-onset Alzheimer's disease (LOAD) in the aged lateral entorhinal cortex. Conversely, mutated genes cause a diffuse cerebral Aßs/Aß-os overproduction promoting early-onset familiar AD (EOFAD). Surplus exogenous Aß-os exert toxic actions at several levels. They reach the nuclei of human astrocyte-neurons teams (ANTs) to enhance the transcription of Aß precursor protein (APP) and ß-secretase/BACE1 genes. The overexpressed APP and BACE1 proteins act in concert with γ-secretase to overproduce endogenous Aßs/Aß-os, of which a few enter the nuclei to upkeep Aßs overproduction, while the rest gather in the cytoplasm, damage mitochondria, and are oversecreted. Simultaneously, extracellular Aß-os bind the ANTs' calcium-sensing receptors (CaSRs) activating signalings that hinder the proteolysis and hence favor the surplus hoarding/secretion of Aßs/Aß-os. Overreleased Aß-os spread, reach growing numbers of adjacent ANTs to recruit them to overproduce/oversecrete further Aß-os amounts via the just mentioned mechanisms. Alongside, Aß•CaSR signalings elicit a noxious overproduction/overrelease of nitric oxide (NO) and vascular endothelial growth factor (VEGF)-A from ANTs' astrocytes. While astrocytes survive the toxic onslaught, neurons die. Thus, AD progression is driven by ceaselessly self-sustaining neurotoxic cycles, which engender first Aß-os and later p-Tau-os that cooperatively destroy increasingly wider cognition-related cortical areas. Notably, a highly selective allosteric CaSR antagonist (calcilytic), like NPS 2143, does preserve human cortical postnatal HCN-1A neurons viability notwithstanding the presence of exogenous Aß-os by suppressing the otherwise elicited oversecretion and spread of newly synthesized Aß-os. Therefore, if given at minimal cognitive impairment or earlier stages, calcilytics could halt AD progression and preserve the patients' cortical neurons, cognitive abilities, and eventually life.

Do astrocytes collaborate with neurons in spreading the "infectious" aß and Tau drivers of Alzheimer's disease?

Evidence has begun emerging for the "contagious" and destructive Aß42 (amyloid-beta42) oligomers and phosphorylated Tau oligomers as drivers of sporadic Alzheimer's disease (AD), which advances along a pathway starting from the brainstem or entorhinal cortex and leading to cognition-related upper cerebral cortex regions. Seemingly, Aß42 oligomers trigger the events generating the neurotoxic Tau oligomers, which may even by themselves spread the characteristic AD neuropathology. It has been assumed that only neurons make and spread these toxic drivers, whereas their associated astrocytes are just janitorial bystanders/scavengers. But this view is likely to radically change since normal human astrocytes freshly isolated from adult cerebral cortex can be induced by exogenous Aß25-35, an Aß42 proxy, to make and secrete increased amounts of endogenous Aß42. Thus, it would seem that the steady slow progression of AD neuropathology along specific cognition-relevant brain networks is driven by both Aß42 and phosphorylated Tau oligomers that are variously released from increasing numbers of "contagion-stricken" members of tightly coupled neuron-astrocyte teams. Hence, we surmise that stopping the oversecretion and spread of the two kinds of "contagious" oligomers by such team members, perhaps via a specific CaSR (Ca(2+)-sensing receptor) antagonist like NPS 2143, might effectively treat AD.

The Aß peptides-activated calcium-sensing receptor stimulates the production and secretion of vascular endothelial growth factor-A by normoxic adult human cortical astrocytes.

The excess vascular endothelial growth factor (VEGF) produced in the Alzheimer's disease (AD) brain can harm neurons, blood vessels, and other components of the neurovascular units (NVUs). But could astrocytes partaking in networks of astrocyte-neuron teams and connected to blood vessels of NVUs contribute to VEGF production? We have shown with cultured cerebral cortical normal (i.e., untransformed) adult human astrocytes (NAHAs) that exogenous amyloid-ß peptides (Aßs) stimulate the astrocytes to make and secrete large amounts of Aßs and nitric oxide by a mechanism mediated through the calcium-sensing receptor (CaSR). Here, we report that exogenous Aßs stimulate the NAHAs to produce and secrete even VEGF-A through a CaSR-mediated mechanism. This is indicated by the ability of Aßs to specifically bind the CaSR, and the capability of a CaSR activator, the "calcimimetic" NPS R-568, to imitate, and of the CaSR antagonist, "calcilytic" NPS 2143, to inhibit, the Aßs stimulation of VEGF-A production and secretion by the NAHAs. Thus, Aßs that accumulate in the AD brain may make the astrocytes that envelop and functionally collaborate with neurons into multi-agent AD-driving "machines" via a CaSR signaling mechanism(s). These observations suggest the possibility that CaSR allosteric antagonists such as NPS 2143 might impede AD progression.

Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous Aß42 prompted by exogenous fibrillary or soluble Aß25-35 in human cortical astrocytes and neurons-therapeutic relevance to Alzheimer's disease.

The "amyloid-ß (Aß) hypothesis" posits that accumulating Aß peptides (Aßs) produced by neurons cause Alzheimer's disease (AD). However, the Aßs contribution by the more numerous astrocytes remains undetermined. Previously we showed that fibrillar (f)Aß25-35, an Aß42 proxy, evokes a surplus endogenous Aß42 production/accumulation in cortical adult human astrocytes. Here, by using immunocytochemistry, immunoblotting, enzymatic assays, and highly sensitive sandwich ELISA kits, we investigated the effects of fAß25-35 and soluble (s)Aß25-35 on Aß42 and Aß40 accumulation/secretion by human cortical astrocytes and HCN-1A neurons and, since the calcium-sensing receptor (CaSR) binds Aßs, their modulation by NPS 2143, a CaSR allosteric antagonist (calcilytic). The fAß25-35-exposed astrocytes and surviving neurons produced, accumulated, and secreted increased amounts of Aß42, while Aß40 also accrued but its secretion was unchanged. Accordingly, secreted Aß42/Aß40 ratio values rose for astrocytes and neurons. While slightly enhancing Aß40 secretion by fAß25-35-treated astrocytes, NPS 2143 specifically suppressed the fAß25-35-elicited surges of endogenous Aß42 secretion by astrocytes and neurons. Therefore, NPS 2143 addition always kept Aß42/Aß40 values to baseline or lower levels. Mechanistically, NPS 2143 decreased total CaSR protein complement, transiently raised proteasomal chymotrypsin activity, and blocked excess NO production without affecting the ongoing increases in BACE1/ß-secretase and γ-secretase activity in fAß25-35-treated astrocytes. Compared to fAß25-35, sAß25-35 also stimulated Aß42 secretion by astrocytes and neurons and NPS 2143 specifically and wholly suppressed this effect. Therefore, since NPS 2143 thwarts any Aß/CaSR-induced surplus secretion of endogenous Aß42 and hence further vicious cycles of Aß self-induction/secretion/spreading, calcilytics might effectively prevent/stop the progression to full-blown AD.

Alzheimer's disease: an update of the roles of receptors, astrocytes and primary cilia (review).

The pathophysiological mechanisms underlying the onset and inexorable progression of the late­onset form of Alzheimer's disease (AD) are still the object of controversy. This review takes stock of some most recent advancements of this field concerning the complex roles played by the amyloid­ß (Aß)­binding p75 neurotrophin receptor (p75NTR) and calcium­sensing receptor (CaSR) and by the primary cilia in AD. Apart from their physiological roles, p75NTR is more intensely expressed in the hippocampus of human AD brains and Aß­bound p75NTR triggers cell death, whereas Aß­bound CaSR signalling induces the de novo synthesis and release of nitric oxide (NO), vascular endothelial growth factor (VEGF)­A and Aß peptides (Aßs), particularly on the part of normal adult human astrocytes. The latter effect could significantly increase the pool of Aß­ and NO­producing nerve cells favouring the progressive spread of a self­sustaining and self­reinforcing 'infectious' mechanism of neural and vascular (i.e. blood-brain barrier) cell damage. Interestingly, primary cilia concentrate p75NTR receptors in their membranes and are abnormally structured/damaged in transgenic (Tg) AD­model mice, which could impact on the adult neurogenesis occurring in the dentate gyrus's subgranular zone (SGZ) that is necessary for new memory encoding, thereby favouring typical AD cognitive decline. Altogether, these findings may pave the way to novel therapeutic approaches to AD, particularly in its mild cognitive impairment (MCI) and pre­MCI stages of development.

The calcium-sensing receptor: a novel Alzheimer's disease crucial target?

Alzheimer's disease (AD) is the most common human neurodegenerative ailment, the most prevalent (>95%) late-onset type of which has a still uncertain etiology. The progressive decline of cognitive functions, dementia, and physical disabilities of AD is caused by synaptic losses that progressively disconnect key neuronal networks in crucial brain areas, like the hippocampus and temporoparietal cortex, and critically impair language, sensory processing, memory, and conscious thought. AD's two main hallmarks are fibrillar amyloid-ß (fAß) plaques in extracellular spaces and intracellular accumulation of fAß peptides and neurofibrillary tangles (NFTs). It is still undecided whether either or both these AD hallmarks cause or result from the disease. Recently, the dysregulation of calcium homeostasis has been advanced as a novel cause of AD. In this case, a suitable candidate of AD driver would be the Aß peptides-binding/activated calcium-sensing receptor (CaSR), whose intracellular signalling is triggered by Aß peptides. In this review, we briefly discuss CaSR's roles in normal adult human astrocytes (NAHAs) and their possible impacts on AD.

Calphostin C, a remarkable multimodal photodynamic killer of neoplastic cells by selective nuclear lamin B1 destruction and apoptogenesis (Review).

Perylenequinones that generate reactive oxygen species (ROS) when illuminated with visible light have been recommended as photodynamic chemotherapeutic agents. One of these is calphostin C (CalC), the action of the photo-activated derivative of which, CalCphiE, has been ascribed to its ability to selectively and irreversibly inhibit protein kinase Cs (PKCs). But recent results of experiments with neoplastic rat fibroblasts and human breast and uterine cervix cancer cells have revealed that the action of CalCphiE involves more than PKC inhibition. Besides suppressing PKC activity, CalCphiE rapidly causes endoplasmic reticulum (ER) stress in breast cancer cells and the selective complete oxidation and proteasomal destruction of the functionally essential nuclear envelope protein lamin B1, in human cervical carcinoma (HCC) cells and neoplastic rat fibroblasts. When these lamin B1-lacking cells are placed in the dark, cytoplasmic membrane-linked PKC activities suddenly rebound and apoptogenesis is initiated as indicated by the immediate release of cytochrome c from mitochondria and later on the activation of caspases. Hence, CalCphiE is a photodynamic cytocidal agent attacking multiple targets in cancer cells and it would be worth determining, even for their best applicative use, whether other perylenequinones also share the so far unexpectedly complex deadly properties of the CalCphiE.

Calcium-sensing receptor (CaSR) in human brain's pathophysiology: roles in late-onset Alzheimer's disease (LOAD).

Although the calcium-sensing receptor (CaSR) is expressed by all types of nerve cells in widespread areas of the human central nervous system (CNS), so far its roles in brain pathophysiology remain largely unknown. Here, we review the available evidence concerning the stages of development of sporadic late-onset Alzheimer's disease (LOAD) and the roles therein played by CaSR signaling. As the brain ages, its ability to dispose of dangerous synapse-targeting soluble amyloid beta-(1-42) (sAbeta42) oligomers released from normal neuronal activity declines. As their levels slowly rise, these oligomers increasingly target and eliminate synapses and prevent synapse formation, thereby eroding the foundations of memory formation and cognitive functions. In this initial stage, neurons, even though synaptically impaired, remain alive. Concurrently, sAbeta42 oligomers by binding to CaSR on human astrocytes induce via mitogen activated protein kinase (MAPK) activity the release of huge amounts nitric oxide (NO), which by itself and after conversion to peroxynitrite (ONOO(-)) damages neighboring neurons. When the sAbeta42 oligomers increasingly aggregate into fibrillar plaques, they attract and activate microglial macrophages that, while trying to clear the plaques, produce via Abeta-activated CaSR signaling several proinflammatory cytokines and reactive oxygen species (ROS). Notably, the microglial cytokines, like sAbeta42 oligomers, induce human astrocytes to make large amounts of NO and hence ONOO(-) via CaSR signal-dependent MAPK activity. The microglial cytokines-activated astrocytes might also produce their own sAbeta42, which would combine with neuron- and microglia-released sAbeta42 to increase the fibrillar burden and promote the further production of reactive oxygen species (ROS), NO/ONOO(-), and proinflammatory cytokines to efficiently kill both normal and functionally impaired (undead) neurons. But, on a somewhat positive note, we speculate that the astrocytes' CaSR-stimulated MAPK activities might also induce vascular endothelial growth factor (VEGF) expression and production. This might in turn enhance neuronal stem cells neurogenesis at least in the subgranular zone (SGZ) of the hippocampal dentate gyrus.

The neuronal primary cilium: driver of neurogenesis and memory formation in the hippocampal dentate gyrus?

Considerable attention has recently been focused on the postnatal persistence of neurogenesis in the dentate gyrus of the hippocampus and the roles of signals from the primary cilium in the different functions of an increasing number of tissues and their malfunctions. Here we summarize the evidence that ties sonic hedgehog-triggered proliferogenic signaling from the primary cilia on granule cell progenitors in the adult dentate subgranular zone to maintain a pool of new "blank slate" dentate granule cells. These can be recruited to bundle and encode novel inputs flowing from various regions of the brain into the dentate gyrus via the entorhinal cortex without altering and erasing the synaptic patterns from previous inputs inscribed on older granule cells.

Calcium, calcium-sensing receptor and colon cancer.

There is much evidence that dietary Ca(2+) loading reduces colon cell proliferation and carcinogenesis in humans and rodents, but during carcinogenesis it becomes ineffective or even tumor-promoting. We are beginning to see how Ca(2+) balances the continuous massive cell production in colon crypts by driving the terminal differentiation and eventually the apoptosis of the cells mainly on the mucosal surface, and how this Ca(2+) control is lost during colon carcinogenesis. The rapid proliferation of the transit-amplifying (TA) progeny of the colon stem cells is driven by the so-called "Wnt" signaling mechanism, which involves the stimulation of proliferogenic genes such as those for c-Myc and cyclin D1 and the silencing of the gene for the cell cycle-stopping p21(Cip1/WAF1) protein by nuclear beta-catenin*Tcf-4 complexes. TA cells avoid mitotic damage and premature apoptosis by expressing the protein survivin. It appears that TA cell cycling stops and terminal differentiation starts when the cells reach a higher level in the crypt where there is enough lumenal Ca(2+) to stimulate the expression and activation of CaSRs (Ca(2+)-sensing receptors), the signals from which stimulate the expression of E-cadherin. Along with this, the APC (adenomatous polyposis coli) protein appears and some of it enters the nucleus. There it makes the TA cells susceptible to the eventual apoptotic balancing by stopping survivin expression and the beta-catenin*Tcf-4 complex from driving further cell cycling by releasing beta-catenin from the nucleus, and delivering it to cytoplasmic APC*axin*GSK-3beta complexes for ultimate proteasomal destruction. Cytoplasmic beta-catenin is then prevented from returning to the nucleus by either being intercepted and destroyed by APC*axin*GSK-3beta complexes or locked by the emerging E-cadherin into membrane adherens junctions which tie the cell into the sheet of proliferatively shut-down cells with APC-dependent cytoskeletons moving to the mouth of the crypt and onto the flat mucosal surface. A common first step in sporadic colon carcinogenesis is the loss of functional APC which disorients upwardly directed migration and causes the retention of nuclear beta-catenin and proliferogenic beta-catenin*Tcf-4 complexes as well as genomic instability. Eventually the balance between cell proliferation and terminal differentiation and death is radically tipped in favour of proliferation by the appearance of apoptosis-resistant, survivin-expressing clones of Ca(2+)-insensitive cells which are locked into the proliferative, mutation-prone mode because of CaSR-disabling gene mutations which prevent the stimulation of E-cadherin expression and terminal differentiation.

Photoexcited calphostin C selectively destroys nuclear lamin B1 in neoplastic human and rat cells - a novel mechanism of action of a photodynamic tumor therapy agent.

Lamin B1, a major component of the nuclear lamina, anchors the nucleus to the cytoskeletal cage, and controls nuclear orientation, chromosome positioning and, alongside several enzymes, fundamental nuclear functions. Exposing polyomavirus-transformed rat pyF111 fibroblasts and human cervical carcinoma (HCC) C4-I cells for 30 min to photoexcited perylenequinone calphostin C, i.e. Cal C(phiE), an established reactive oxygen species (ROS)-generator and protein kinase C (PKC) inhibitor, caused the cells to selectively oxidize and then totally destroy their nuclear lamin B1 by only 60 min after starting the treatment, i.e. when apoptotic caspases' activities had not yet increased. However, while the oxidized lamin B1 was being destroyed, lamins A/C, the lamin A-associated nuclear envelope protein emerin, and the nucleoplasmic protein cyclin E were neither oxidized nor destroyed. The oxidized lamin B was ubiquitinated and demolished in the proteasome probably by an enhanced peptidyl-glutaminase-like activity. Hence, the Cal C(phiE)-induced rapid and selective lamin B1 oxidation and proteasomal destruction ahead of the activation of apoptotic caspases was by itself a most severe molecular lesion impairing vital nuclear functions. Conversely, Cal C directly added to the cells kept in the dark damaged neither nuclear lamin B1 nor cell viability. Thus, our findings reveal a novel cell-damaging mechanism of a photodynamic tumor therapeutic agent.

Emerging concepts of how ß-amyloid proteins and pro-inflammatory cytokines might collaborate to produce an 'Alzheimer brain' (Review).

Three steps lead to the development of full-blown sporadic or late-onset Alzheimer's disease or dementia (AD). In the young brain, amyloid ß-(1-42) (Aß 42) is a normal aggregation-prone protein product of neuronal activity that is kept at a safe low level by proteolysis in neurons and glial cells, and by expulsion across the blood-brain barrier. But clearance declines with advancing age. Step 1: Because of the normal decline with age of the Aß 42-clearing mechanisms, toxic amyloid-derived diffusible ligands (ADDLs) made of dodecamers of the aggregation-prone Aß 42 start accumulating. These Aß 42 dodecamers selectively target the initially huge numbers of excitatory synapses of neurons and cause them to start slowly dropping, which increasingly impairs plasticity and sooner or later starts noticeably affecting memory formation. At a certain point, this increasing loss of synapses induces the neurons to redirect their still-expressed cell cycle proteins from post-mitotic jobs, such as maintaining synapses, to starting a cell cycle and partially or completely replicating DNA without entering mitosis. The resulting aneuploid or tetraploid neurons survive for as long as 6-12 months as quasi-functional 'undead zombies', with developing tangles of hyperphosphorylated τ protein disrupting the vital anterograde axonal transport of mitochondria and other synapse-vital components. Step 2: The hallmark AD plaques appear as Aß 42 clearance continues to decline and the formation of Aß 42 non-diffusible fibrils begins in the aging brain. Step 3: A terminal cytokine-driven maëlstrom begins in the aging brain when microglia, the brain's professional macrophages, are activated in and around the plaques. They produce pro-inflammatory cytokines, such as IFN-γ, IL-1ß and TNF-α. One of these, IFN-γ, causes the astrocytes enwrapping the neuronal synapses to express their ß-secretase (BACE1) genes and produce and release Aß 42, which can kill the closely apposed neurons by binding to their p75NTR receptors, which generate apoptogenic signals. Astrocytes are also stimulated by the same cytokines to turn on their nitric oxide synthase (NOS)-2 genes and start pouring large amounts of nitric oxide (NO) and its cytocidal derivative peroxynitrite (ONOO-) directly out onto the closely apposed neurons.

The road to LOAD: late-onset Alzheimer's disease and a possible way to block it.

The ageing brain becomes increasingly less able to destroy or eject toxic amyloid (A) beta42 peptide byproducts of normal neuronal activity that consequently accumulate to induce Alzheimer's disease (AD). Therefore, the various components of the Abeta-clearing machinery are prime targets for AD therapeutics. In this connection, there are reports that taking statins to lower circulating cholesterol to prevent cardiovascular disease can also prevent late-onset AD (LOAD) the most common form of the disease. However, it seems unlikely that statins would prevent LOAD by lowering the very long-lived brain cholesterol that is controlled independently from the very much shorter-lived circulating cholesterol. In fact, reducing the ability of the brain astrocytes to make cholesterol for their closely associated neuron clients' synaptogenesis could damage the brain rather than protect it. However, a plausible way statins might prevent LOAD is to target a main component of the clearance machinery, low-density lipoprotein receptor-related protein 1 (LRP1), the brain's powerful Abeta-efflux driver. This is indicated by a reported ability of micromolar concentrations of lovastatin and simvastatin to strongly stimulate brain vascular endothelial cells to make this Abeta ejector. Therefore, if this holds up, taking a statin over the years would prevent the normal decline of LRP1 in the ageing brain and a LOAD-driving accumulation of Abeta.

Can statins put the brakes on Alzheimer's disease?

Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which initiates the syntheses of cholesterol and isoprenoid lipids that are needed to provide amyloid peptides for the amyloid cascade. This cascade is believed to induce sporadic or late-onset Alzheimer's disease, which accounts for 90 - 95% of Alzheimer's disease sufferers. Cholesterol is also the prime driver of cerebrovascular disease that (along with amyloid peptides) increasingly appears to be linked to the cognitive deterioration of Alzheimer's disease. Cholesterol is needed to make the lipid rafts that are the platforms for isoprenoid-dependent assembly and activation of raftophilic beta- and gamma-secretases that work in tandem to excise dangerous 40 and 42 amino acid amyloid-beta (Abeta) fragments from amyloid precursor protein, the transmembrane amyloid precursor glycoprotein. When they are excessively produced and can no longer be effectively destroyed or otherwise cleared from the hypoperfused ageing brain, the Abeta42 fragments released from the active synaptic terminals of normally busy neurons (and from stressed neurons unsuccessfully trying to proliferate and producing disruptive tangles of hyperphosphorylated tau-proteins) aggregate into neuritic plaques, which activate glial cells. The pro-inflammatory cytokines and growth factors from the glial cells further damage and kill neurons. As statins strike at several parts of the Alzheimer's disease mechanism (such as the infliction of cholesterol-dependent cerebrovascular damage) by inhibiting HMG-CoA reductase, their long-term use (starting as early as possible during Alzheimer's disease development) should slow or even prevent the progression of Alzheimer's disease. Indeed, there is some evidence of a significantly reduced incidence of Alzheimer's disease among people who have been using statins to reduce hypercholesterolaemia and its cardiovascular effects. To be certain of this, there must be more multi-year trials to specifically assess the effects of statins on sporadic Alzheimer's disease.

Osteoporosis-treating parathyroid hormone peptides: What are they? What do they do? How might they do it?

The first experiments demonstrating parathyroid hormone's (PTH's) dramatic bone-building activity in rat pups, using a bovine parathyroid extract called parathormone were reported 74 years ago. Over the next decades, the native parathyroid hormone (human (h)PTH(1-84)) was purified and two of its fragments (hPTH(1-34) and (Leu27)cycloGlu22-Lys26hPTH(1-31)NH2) have been developed for the treatment of osteoporosis. One of these, recombinant (r)hPTH(1-34), is now on the market under the trade name of Forteo. The native hormone has also completed clinical trials and (Leu27)cycloGlu22-Lys26hPTH(1-31)NH2 is in phase II clinical trials under the trade name Ostabolin-C. All three of these peptides potently stimulate bone growth, reinforce bone microstructure weakened by estrogen deprivation and reduce further fracturing. Furthermore, future studies may demonstrate that these peptides also promote the repair of existing fractures and implant anchorage in both healthy and osteoporotic humans. PTHs have the potential to become more successful by using cost-cutting, but still effective, cyclical treatment regimens and by formulating them for non-injectable delivery. This review will discuss the identification of PTH peptides, how they function and their future role in the treatment of osteoporosis.

Parathyroid hormone: a novel tool for treating bone marrow depletion in cancer patients caused by chemotherapeutic drugs and ionizing radiation.

Between 1958 and the late 1970s it was learned that PTH (the parathyroid hormone) could directly stimulate the initiation of DNA replication by murine CFU-S (colony-forming unit-spleen) cells via cyclic AMP, stimulate the proliferation of normal and X-irradiated murine and rat bone marrow cells, control hematopoiesis, and increase the survival of X-irradiated mice and rats when injected any time between 18h before and 3h after X-irradiation. Since then, it has been shown that the hematopoietic stem cell niche consists of PTH receptor-bearing, osteoblastic trabecular bone-lining cells that maintain the stem cells' (HSCs') proliferatively quiescent 'stemness' by various gene up-regulating and down-regulating signals caused by the tight adhesion of the HSCs to the osteoblastic niche-lining cells. Stimulating the osteoblastic lining cells with recombinant human PTH-(1-34) (Forteo) causes a cyclic AMP-mediated enlargement of the HSC pool and promotes bone marrow transplant engraftment and growth and the survival of lethally irradiated mice. But this is only the beginning of the exploitation of the PTHs for marrow engraftment. It must now be determined whether the marrow engraftment-enhancing action of this potent bone growth-stimulating PTH can be extended from mice to rats and monkeys. It must be determined whether two other PTH peptides, rhPTH-(1-84) [Preos]and [Leu(27)]cyclo(Glu(22)-Lys(26))hPTH-(1-31)NH(2) [Ostabolin-C]) are as effective as or better than rhPTH-(1-34)(Forteo). Since, all three peptides are on the market, or nearing the market, for safely and strongly stimulating bone growth and treating osteoporosis one or all of them may become valuable tools for safely promoting the engraftment of peripherally harvested HSCs in cancer patients whose bone marrows have been 'emptied' by chemotherapeutic drugs or ionizing radiation.

VP-16 (etoposide) and calphostin C trigger different nuclear but akin cytoplasmic patterns of changes in the distribution and activity of protein kinase C-betaI in polyomavirus-transformed pyF111 rat fibroblasts.

Protein kinase C (PKC) isoforms regulate cell proliferation and apoptosis. Since the PKC isoenzyme complement varies considerably from cell type to cell type, a PKC's responsiveness to an apoptogenic challenge must be defined for both the type of apoptogen and the type of cell. We have already reported that the changes in the distribution and activity of PKC-delta in apoptosing polyomavirus-infected/transformed Fischer rat embryo pyF111 fibroblasts depend on the type of apoptogen. Here, we show that this is also true for PKC-betaI in pyF111 cells treated with the slow DNA-damaging VP-16 (etoposide) or the fast-acting (in the cytoplasm) calphostin C. These apoptogens caused quite different shifts of the PKC-betaI level and activity in the nuclear membrane (NM) and nucleoplasm (NP), but corresponding changes in the cytosol (CS) and cytoplasmic particulate (CP) fractions. The hefty translocation of PKC-betaI onto the CP fraction and its increased activity there suggest the possible triggering of a cytochrome c/caspase-mediated apoptosis-inducing mechanism common to both agents. The present results are a necessary lead-up to functional proteomic analyses aimed at identifying the molecules forming the local PKC-betaI signalling modules under different conditions.