Current Alzheimer Research - Volume 3, Issue 1, 2006

Current Alzheimer Research enters the third year of successful publication with a great sense of satisfaction and accomplishment. All five issues of its second volume were completed and published on time, as promised. The second volume featured a total of 65 articles, a 100% jump from its previous volume. These articles, which are comprised of primary research and review work, were written by experts in the field of Alzheimer's disease (AD) and duly peerreviewed prior to publication. In total, this work was a contribution by researchers from 19 countries: Australia, Canada, Chile, China, Cuba, Denmark, France, Germany, Hungary, Israel, Japan, Netherlands, Poland, Portugal, Spain, Switzerland, Taiwan, UK and the USA. The journal, hence, remains a truly international one - covering diverse aspects of research related to AD. The success of the journal has been recognized by its acceptance for listing in Pub- Med/MEDLINE databases. This constitutes a milestone event for Current Alzheimer Research. In addition to the print format, it is accessible via online (http://www.bentham.org/car/). Abstracts of the articles are freely available on the journal's website. Furthermore, the journal has expanded its Editorial Advisory Board (EAB) by including several renowned experts in the arena of neuroscience and AD. The key and important aspect of this journal concerns reporting a combination of mechanistic and translational studies that encompass a wide range of AD research, such as amyloid biology, apolipoprotein E, apoptosis, brain imaging, immunotherapy, genetics, statins and tauopathy. The journal has also reported studies from clinical drug trials. Interestingly, during the last single year, alone, the AD research field has burst with activity - as evident from the listing of approximately 4,000 papers on MEDLINE. Thus, the necessity of timely dissemination of this knowledge can never be greater. Current Alzheimer Research can expertly cover a fraction of primary research; however, the journal's 'review' articles provide a comprehensive overview of selected high interest topics and remain an invaluable resource for the AD field. In the third volume, with 5 different issues, Current Alzheimer Research plans to present a wide range of topics, as critical review articles or original research reports, which will address the molecular basis of the disease, potential drug targets, and therapeutic strategies for AD. The journal will present research from a combination of appropriate cellular, genetic, and in vivo models. In the 3rd volume, we also plan to publish special issues written by experts on different hot topics, such as apoptotic mechanisms in AD, as well as on the current understanding of AD therapeutics - based on the upcoming '9th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy'. Our major goals in the 3rd volume are to continue to report cutting edge research on AD from biochemical, epidemiological and neuroscience studies, and to provide an insightful summary of important advances in AD research with an emphasis on potential drug development strategies. The 3rd volume (issue 1) begins with a special issue entitled, "Neurogenesis as a Therapeutic Strategy for Cognitive Aging and Alzheimer's Disease", and is ably edited by Gunnar Gouras and Howard Fillit. This issue contains 11 articles, which address one of the most interesting and relevant topics in the field of neurodegenerative disorders, neurogenesis, especially its role in the pathogenesis of AD and its potential utility as a valid target for the therapy of AD. In addition, this issue presents an interesting "Debate section" with three papers that both argue and present major novel hypotheses to explain the fundamental pathobiochemical events occurring in AD: i) the amyloid cascade hypothesis; ii) an alternative to the amyloid beta hypothesis; and iii) a faulty protein-turnover model. Further models, ideas and hypotheses will, additionally, be discussed in future issues to stimulate research and build the road to cure this scourge. On behalf of the Editorial Board and the Bentham Science Publishers, I deeply appreciate the enormous support received from the readers, authors, reviewers, sponsors and the neuroscience community. I truly believe that the journal will continue to make great progress with all of your invaluable support and patronage. I welcome your comments, advice, and suggestions to further improve this journal, and also solicit review papers, and original reports in the numerous diverse areas of AD research. It has been an exciting journey of knowledge to unlock the mysteries of Alzheimer's disease and I thank you all for both your company and contributions.

The discovery of small molecules capable of promoting neurogenesis will contribute to the elucidation of the physiological roles of neurogenesis and to novel therapeutic approaches. Small molecule development can be targeted to the promotion of precursor proliferation, survival, migration or maturation and might be applied to augmenting physiological neurogenesis already present in the dentate gyrus or subventricular zone/olfactory bulb or to normally nonneurogenic regions relevant to neuropathological states. Current small molecule discovery can be assessed from the perspective of the following categories: compounds modulating physiological signaling pathways regulating neurogenesis including the sonic hedgehog, bone morphogenic protein Wnt/,-catenin, Notch and chemokine systems; growth factor mimetics; protein tyrosine phosphatase inhibitors; existing drugs including antidepressants, lithium, valproate, sidenafil and statins; hormones, steroids and peptides; and neurotransmitter receptor agonists and antagonists. Unbiased, high throughput screening will likely lead to the discovery of additional active compounds and the recognition of novel mechanisms regulating neurogenesis. A major therapeutic challenge will consist of the identification of molecular targets and mechanisms relatively specific for precursor cells of interest.

Herein, we present data to support a preclinical proof of concept for the therapeutic potential of allopregnanolone to promote neurogenesis. Our recent work has demonstrated that the neuroactive progesterone metabolite, allopregnanolone (3α-hydroxy-5α-pregnan-20-one), (APα) induced, in a dose dependent manner, a significant increase in proliferation of neuroprogenitor cells (NPCs) derived from the rat hippocampus and human neural stem cells (hNSM) derived from the cerebral cortex [1]. Proliferative efficacy was determined by incorporation of BrdU and 3H-thymidine, FACS analysis of MuLV-GFP-labeled mitotic NPCs and quantification of total cell number. Allopregnanolone-induced proliferation was isomer and steroid specific, in that the stereoisomer 3β-hydroxy-5β-pregnan-20-one and related steroids did not increase 3H-thymidine uptake. Immunofluorescent analyses for the NPC markers, nestin and Tuj1, indicated that newly formed cells were of neuronal lineage. Furthermore, microarray analysis of cell cycle genes and real time RT-PCR and western blot validation revealed that allopregnanolone increased the expression of genes which promote mitosis and inhibited the expression of genes that repress cell proliferation. Allopregnanolone-induced proliferation was antagonized by the voltage gated L-type calcium channel blocker nifedipine consistent with the finding that allopregnanolone induces a rapid increase in intracellular calcium in hippocampal neurons via a GABA type A receptor activated L-type calcium channel. Preliminary in vivo data indicate that APα for 24 hrs significantly increased neurogenesis in dentate gyrus, as determined by unbiased stereological analysis of BrdU positive cells, of 3-month-old male triple transgenic Alzheimer's disease mice. The in vitro and in vivo neurogenic properties of APα coupled with a low molecular weight, easy penetration of the blood brain barrier and lack of toxicity, are key elements required for developing APα as a neurogenic / regenerative therapeutic for restoration of neurons in victims of Alzheimer's disease.

The neurotrophins mediate diverse actions in the developing peripheral and central nervous systems. They are initially synthesized as precursor forms, or proneurotrophins, that are cleaved to release C-terminal mature forms that bind to Trk receptor tyrosine kinases to enhance synaptic plasticity and neuronal survival. Recent studies suggest that proneurotrophins are not inactive precursors, but signaling proteins that can activate the p75 receptor to mediate diverse responses. Proneurotrophins can activate a heteromeric receptor complex of p75 and sortilin to initiate cell death, or bind to p75 in hippocampal neurons to enhance long term depression. Thus, neurotrophin actions are regulated by the form of the neurotrophin (pro- or mature) secreted by cells, by extracellular proteolytic cleavage of proneurotrophins to generate mature forms, and by the expression of neurotrophin receptors Trk, or p75 and sortilin, that are selectively activated by mature or proneurotrophins, respectively. Here, recent studies are reviewed that reveal that pro- and mature neurotrophins have distinct and sometimes opposing actions in regulating cell death and survival in development and in pathophysiologic states, in regulating neurotrophin secretion, and in modulating synaptic plasticity.

Neurogenesis, or the production of new neurons from neuronal precursor cells, is a normal phenomenon in the adult brain, and is accentuated by brain injury. Forms of injury associated with increased neurogenesis include both acute (e.g., stroke) and chronic neurodegenerations. Studies on human postmortem material and transgenic mice overexpressing amyloid precursor protein mutations found in familial Alzheimer's disease (AD) suggest that AD is associated with enhanced neurogenesis. However, the mechanism responsible for this effect is unknown, as is what influence it may have on the clinical course of murine or human AD. If AD leads to the production of fully functional, mature neurons that can restore brain function, strategies aimed at further increasing endogenous neurogenesis may have therapeutic value.

Rodents housed in an enriched environment, exercise by running or perform learning and memory tasks show an increase in hippocampal neurogenesis. We show that both environmental enrichment, as well as performance in the Morris water maze, a hippocampal-dependent learning task, leads to an increase in local VEGF expression in rats. We genetically recreated this situation by somatic cell gene transfer using recombinant adeno-associated virus (AAV) vectors. Genetically increasing hippocampal VEGF in adult rats resulted in a ∼2 fold increase in neurogenesis associated with improved cognition. In contrast, gene transfer of placental growth factor (PGF) which signals through Flt1, but not KDR receptors had negative effects on neurogenesis and inhibited learning, although it similarly increased endothelial cell proliferation. Expression of a dominant negative, mKDR, inhibited basal neurogenesis and impaired learning. Co-expression of mKDR antagonized VEGF-enhanced neurogenesis and learning without inhibiting endothelial cell proliferation. Furthermore, inhibition of VEGF expression by RNA interference completely blocked the environmental induction of neurogenesis. These data support a model whereby VEGF acting via KDR is a mediator of the effect of the environment on neurogenesis and cognition [1].

Studies on oligodendrocytes, the myelin-forming cells of the central nervous system, and on the progenitor cells from which they are derived, have provided several novel insights into the role of intracellular redox state in cell function. A central unifying theme of this research is that redox state modulation lies at the heart of understanding cellintrinsic aspects of precursor cell function, responsiveness of precursor cells to cell-extrinsic signals and even the means by which cell-extrinsic signaling molecules alter cellular function. This review discusses our studies on the role in redox state as a critical modulator of cellular function, and considers the implications of these findings for optimizing tissue repair.

Age is the biggest risk factor for the development of neurodegenerative diseases. Consequently, as the population ages it becomes more critical to find ways to avoid the debilitating cost of neurodegenerative diseases such as Alzheimer's. Some of the non-invasive strategies that can potentially slow down the mental decline associated with aging are exercise and use of multi-sensory environmental stimulation. The beneficial effects of both exercise and multi-sensory environmental stimulation have been well-documented, thus it is possible that these strategies can either provide neuroprotection or increase resistance to the development of age-related cognitive problems.

Many researchers have questioned whether new potential therapies aimed at reversing Alzheimer's disease (AD) are indeed scientifically feasible. A number of approved therapies already exist for Alzheimer's disease, yet these drugs only slow the disease progression for a period of time and treat the symptoms of this devastating disease. New therapies intended to reverse the disease would necessarily need to replace dead, dying and dysfunctional neurons in affected regions of the brain. This complex drug discovery problem is further complicated by the knowledge that AD is mainly an aging disorder and that aging, though not considered a disease, causes biological changes that may also need to be overcome [1]. The requirement for new, functional neurons under neurodegenerative diseases, as seen in AD and stroke suggests that an inhibitor of neuronal death, like Memantine, is insufficient to reverse the cognitive and physical loss. New neurons, or neurogenesis, may be required for real improvement or reversal of the cognitive deficit. Adult neurogenesis, first described by Altman in the early 1960s [2, 3], has more recently been observed as a response to injury or disease. Of interest was the finding that new neurons appear to migrate to disease/injury-affected areas in the brain not normally neurogenic in the adult. This pathological-stimulation of neurogenesis does not appear sufficient to stave off the disease and subsequent behavioral decline. Therefore, the desire to amplify and improve upon the neurogenesis-response to neurodegenerative disease appears warranted, if not yet feasible. The key to doing so lies in identifying what signals are required to promote neurogenesis and neuron survival, either in injury and disease or under environmental stimuli. This could provide clues for how to pharmacologically induce neurogenesis under neurodegenerative conditions. Currently, progress in identifying therapeutics that appear to promote ameliorative neurogenesis for AD is lagging behind the pharmacological induction of neurogenesis as a therapy for depression.

The remediation of neurodegeneration and cognitive decline in Alzheimer's Disease (AD) remains a challenge to basic scientists and clinicians. It has been suggested that adult bone marrow stem cells can transdifferentiate into different neuronal phenotypes. Here we demonstrate that the a-secretase-cleaved fragment of the amyloid precursor protein (sAPPα), a potent neurotrophic factor, potentiates the nerve growth factor (NGF)/retinoic acid (RA) induced transdifferentiation of bone marrow-derived adult progenitor cells (MAPCs) into neural progenitor cells and, more specifically, enhances their terminal differentiation into a cholinergic-like neuronal phenotype. The addition of sAPPa to NGF/RAstimulated MAPCs resulted in their conversion to neuronal-like cells as evidenced by the extension of neurites and the appearance of immature synaptic complexes. MAPCs differentiated in the presence of sAPPα and NGF/RA exhibited a 40% to as much as 75% increase in neuronal proteins including NeuN, β;-tubulin III, NFM, and synaptophysin, compared to MAPCs differentiated by NGF/RA alone. This process was accompanied by an increase in the levels of choline acetyltransferase, a marker of cholinergic neurons, compared to those of GABAergic and dopaminergic neuronal subtypes. MAPCs immunpositive for sAPP&a were identified within the septohippocampal system of transgenic PS/APP mice injected intravenously with sAPPa-transfected MAPCs and found in close proximity to the cerebral vasculature. Given that in AD cholinergic neurons are severely vulnerable to neurodegeneration and that the levels of sAPPa are significantly reduced, these findings suggest the combined use of sAPPα and MAPCs offers a new and potentially powerful therapeutic strategy for AD treatment.

After much initial debate for and against the role of amyloid in Alzheimer's disease (AD), mutations on the amyloid precursor protein (APP) and processing pathways that increase levels of the amyloid b peptide of 42 residues (Aβ42) have established that faulty function or processing of these proteins are responsible for AD pathogenesis. Given the neurotoxicity of aggregates of Ab42, the central role of this peptide in AD pathogenesis is self evident. In this article, I summarize the major pieces of evidence adduced to support the amyloid cascade hypothesis and point out their limitations

Alzheimer disease (AD) is a devastating condition and patients, caregivers, clinicians, and scientists are eager to decipher the underlying disease mechanism and, thereafter, target this therapeutically. Most investigators studying the underlying cause of AD have focused on amyloid-β (Aβ) such that the Amyloid Cascade Hypothesis is the predominant mechanism thought to be responsible for the disease. However, a number of caveats have led us to seriously question the validity of this hypothesis. First, in addition to increases in Aβ, genetic mutations in AD lead to increased vulnerability to oxidative/apoptotic insults indicating that the mutated protein disturbs redox balance. Whether mutations result in Aβ deposition that then causes oxidative stress or whether mutations cause oxidative stress that results in Aβ deposition is unclear. Indeed, while in vitro experiments show that Ab can directly cause oxidative stress to cells in culture, it is apparent from other studies that the reverse is also true, namely that oxidative stress leads to increases in Aβ. Notably, in vivo studies in both sporadic and genetic forms of the disease show that oxidative stress temporally precedes increases in Aβ and that increases in Aβ are associated with a decrease in oxidative stress. Based on these findings, we herein propose an Alternate Amyloid Hypothesis in which pathogenic factors for disease lead to increased oxidative stress that then leads to increases in Aβ. Further, we propose that Aβ serves as a redox sensor and that oxidatively-induced Ab serves to attenuate oxidative stress. Obviously, whether Ab is the culprit, as argued by the Amyloid Cascade Hypothesis, or a much maligned protector, as argued by the Alternate Amyloid Hypothesis, is clearly important to decipher to advance our understanding and design efficacious therapeutics for this disease.

The amyloid hypothesis has dominated the thinking in our attempts to understand, diagnose and develop drugs for Alzheimer's disease (AD). This article presents a new hypothesis that takes into account the numerous familial AD (FAD) mutations in the amyloid precursor protein (APP) and its processing pathways, but suggests a new perspective beyond toxicity of forms of the amyloid β-peptide (Abgr;). Clearly, amyloid deposits are an invariable feature of AD. Moreover, although APP is normally processed to secreted and membrane-bound fragments, sAPPbgr; and CTFb, by BACE, and the latter is subsequently processed by γ-secretase to Abgr; and CTFγ, this pathway mostly yields Ab of 40 residues, and increases in the levels of the amyloidogenic 42-residue Abgr; (Abgr;42) are seen in the majority of the mutations linked to the disease. The resulting theory is that the disease is caused by amyloid toxicity, which impairs memory and triggers deposition of the microtubule associated protein, Tau, as neurofibrillary tangles. Nevertheless, a few exceptional FAD mutations and the presence of large amounts of amyloid deposits in a group of cognitively normal elderly patients suggest that the disease process is more complex. Indeed, it has been hard to demonstrate the toxicity of Abgr;42 and the actual target has been shifted to small oligomers of the peptide, named Ab derived diffusible ligands (ADDLs). Our hypothesis is that the disease is more complex and caused by a failure of APP metabolism or clearance, which simultaneously affects several other membrane proteins. Thus, a traffic jam is created by failure of important pathways such as γ-secretase processing of residual intramembrane domains released from the metabolism of multiple membrane proteins, which ultimately leads to a multiple system failure. In this theory, toxicity of Abgr;42 will only contribute partially, if at all, to neurodegeneration in AD. More significantly, this theory would predict that focussing on specific reagents such as γ-secretase inhibitors that hamper metabolism of APP, may initially show some beneficial effects on cognitive performance by elimination of acutely toxic ADDLs, but over the longer term may exacerbate the disease process by reducing membrane protein turnover.