Targeting Synaptic Dysfunction in Alzheimer's Disease
Posted July 22, 2011
Alzheimer's disease is generally described as a disease of amyloid plaques and tau tangles—sticky clumps of protein that interfere with and ultimately kill neurons. While these two pathogenic processes do seem to be involved in neurodegeneration and cell death, this theory does not explain all facets of the disease. Analyzing dysfunction in the synapse, the regions where two nerve cells meet and communicate, may provide important new insights into the onset and progress of this common form of dementia, said Howard Fillit, organizer of a May 18, 2011, symposium, "Targeting Synaptic Dysfunction in Alzheimer's Disease," cosponsored by the Alzheimer's Drug Discovery Foundation and the Brain Dysfunction Discussion Group of the New York Academy of Sciences.
One of the major weaknesses of the prevailing "amyloid theory" of AD is that amyloid load in the brain is related only loosely to cognitive decline. This observation raises the possibility that even if the amyloid-clearing treatments now being tested as AD therapeutics do effectively remove plaque from the brain, they may not alleviate symptoms of the disease. In contrast, synaptic loss is well correlated with cognitive impairment. Evidence suggests that synaptic degradation precedes amyloid buildup, suggesting that synaptic proteins may make good targets for intervention early on in the disease.
The scientists at the symposium presented work characterizing the changes at the synapse and the effects of diet and exercise on synaptic dysfunction in Alzheimer's disease. Other researchers presented their work on a wide range of mechanisms that may result in synaptic dysfunction including aberrant intracellular signaling in neurons exposed to amyloid-β, lipid imbalances at the membrane, and activation of prion protein through its interactions with amyloid-β.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations available from:
Ottavio Arancio, MD, PhD (Columbia University)
Gilbert Di Paolo, PhD (Columbia University)
Howard M. Fillit, MD (Alzheimer's Drug Discovery Foundation)
Vahram Haroutunian, PhD (Mount Sinai School of Medicine)
Barbara L. Hempstead, MD, PhD (Weill Cornell Medical College)
Eric Klann, PhD (New York University)
Mark P. Mattson, PhD (National Institute on Aging)
Grace E. Stutzmann, PhD (Rosalind Franklin University / The Chicago Medical School)
This event was funded in part by the Life Technologies™ Foundation.
- 00:011. Introduction
- 04:172. BDNF delivery; Study history
- 11:093. Alterations in BDNF resulting in significant phenotypes
- 15:484. Utilizing gene delivery to enhance neurotrophin expression; TrkB activation
- 20:135. Proneurotrophins; Expression of proNGF in neurodegenerative disease
- 28:376. Conclusion and acknowledgement
- 00:011. Introduction
- 03:002. ROS, oxidative stress, and aging; EC-SOD TG mouse study
- 06:173. Superoxide dismutases; SOD-2 TG mouse studies
- 12:464. Prevention of A-beta-induced impairment in LTP and MitoQ
- 16:055. The targets of ROS that impair LTP and memory function; eIF2
- 22:286. Summary; Acknowledgements and conclusio
- 00:011. Introduction
- 05:502. Glutamate, calcium, and neurotrophic factors; Glucose deprivation
- 10:213. Modification of neural vulnerability; Triple-transgenic mouse model
- 19:364. Adaptive plasticity and stress responses; ERK and CREB activation
- 25:415. Base excision repair; Diabetes and cognitive function
- 34:026. GLP-1 study; Clinical trial of Exendin-4; Acknowledgements and conclusio
- 00:011. Introduction and overview
- 04:342. Structural diversity of lipids; Lipidomic profiling
- 11:503. Cholesterol esters and ACAT inhibitors; DAG metabolism in AD
- 17:064. Effects of synthetic A-beta42 oligomers; PIP2 to PIP conversion; Synj1 haploinsufficiency
- 24:405. Conclusions and acknowledgment
- 00:011. Introduction; Alzheimer's two forms
- 04:422. Early signaling mechanisms; Enhanced ER Ca2+ release; RyR2 isoform
- 12:483. Altered RyR-calcium signaling and mutant PS1-expressing neurons
- 16:424. NMDAR-mediated calcium influx; Hippocampal LTP and LTD at CA3-CA1 synapse
- 24:225. Effects of dysregulated ER calcium signaling on synaptic transmission and plasticity
- 31:506. Blocking or reversing the effects; Summary and conclusion
The Alzheimer's Association
The Alzheimer's Association presents statistics, basic facts about the disease, as well as information about grants and schedules for ICAD, the annual meeting on dementia research.
The Alzheimer Research Forum
The Alzheimer Research Forum offers resources for scientists who study the molecular mechanisms of this neurodegenerative disease. In particular, a few journal articles about changes in synaptic function were chosen as "papers of the week," with relevant discussions, such as a 2009 paper about A-β related synaptotoxicity, and a discussion of evidence that oligomers interfere with NMDA receptor function.
Haroutunian V, Schnaider-Beeri M, Schmeidler J, et al. Role of the neuropathology of Alzheimer disease in dementia in the oldest-old. Arch. Neurol. 2008;65(9):1211-7.
Katsel P, Tan W, Haroutunian V. Gain in brain immunity in the oldest-old differentiates cognitively normal from demented individuals. PLoS One 2009;4(10):e7642.
Calabrese V, Cornelius C, Dinkova-Kostova AT, et al. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid. Redox. Signal 2010;13(11):1763-811.
Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol. 2011;10(2):187-98. Erratum in: Lancet Neurol. 2011;10(2):115.
Mattson MP. The impact of dietary energy intake on cognitive aging. Front. Aging Neurosci. 2010;2:5.
Bruno AM, Huang JY, Bennett DA, et al. Altered ryanodine receptor expression in mild cognitive impairment and Alzheimer's disease. Neurobiol. Aging 2011.
Goussakov I, Miller MB, Stutzmann GE. 2010. NMDA-mediated Ca(2+) influx drives aberrant ryanodine receptor activation in dendrites of young Alzheimer's disease mice. J. Neurosci. 2010;30(36):12128-37.
Puzzo D, Staniszewski A, Deng SX, et al. Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer's disease mouse model. J. Neurosci. 2009;29(25):8075-86.
Hempstead BL. Commentary: Regulating proNGF action: multiple targets for therapeutic intervention. Neurotox. Res. 2009;16(3):255-60.
Teng KK, Felice S, Kim T, Hempstead BL. Understanding proneurotrophin actions: Recent advances and challenges. Dev. Neurobiol. 2010;70(5):350-9. Review.
Chang-Ileto B, Frere SG, Chan RB, et al. Synaptojanin 1-mediated PI(4,5)P2 hydrolysis is modulated by membrane curvature and facilitates membrane fission. Dev. Cell 2011;20(2):206-18.
Di Paolo G, Kim TW. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat. Rev. Neurosci. 2011;12(5):284-96. Review.
Gimbel DA, Nygaard HB, Coffey EE, et al. Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J. Neurosci. 2010;30(18):6367-74.
Gunther EC, Strittmatter SM. β-amyloid oligomers and cellular prion protein in Alzheimer's disease. J. Mol. Med. 2010;88(4):331-8. Review.
Ma T, Hoeffer CA, Wong H, Massaad CA, et al. Amyloid β-induced impairments in hippocampal synaptic plasticity are rescued by decreasing mitochondrial superoxide. J. Neurosci. 2011;31(15):5589-95.
Massaad CA, Washington TM, Pautler RG, Klann E. Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 2009;106(32):13576-81.
He G, Luo W, Li P, et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 2010;467(7311):95-8.
Howard M. Fillit, MD
Howard Fillit, a geriatrician, neuroscientist, and leading expert in Alzheimer's disease, is the founding Executive Director of the Alzheimer's Drug Discovery Foundation. Fillit has had a distinguished academic medicine career at The Rockefeller University and The Mount Sinai School of Medicine where he is currently a clinical professor of geriatrics, medicine and neuroscience. From 1995–1998, he was the corporate medical director for Medicare at New York Life, providing program leadership for over 125,000 elderly people in several regional U.S. markets. Throughout his career, Fillit has maintained a limited private practice in Manhattan in consultative geriatric medicine with a focus on Alzheimer's disease. He has also served as a consultant to pharmaceutical and biotechnology companies, health care organizations, and philanthropies. He is the author or co-author of more than 300 scientific and clinical publications, and is the senior editor of the leading international Textbook of Geriatric Medicine and Gerontology. Fillit has received several awards and honors including the Rita Hayworth Award for Lifetime Achievement.
Sonya Dougal, PhD
The New York Academy of Sciences
Sonya Dougal is a Program Manager of the Life Sciences Programs at the New York Academy of Sciences. Prior to joining the Academy in 2008, she conducted market research at Eric Marder Associates in New York City. Dougal received her scientific training in cognitive neuroscience as a Ruth L. Kirschstein NRSA postdoctoral fellow at New York University, in the laboratory of Elizabeth Phelps, and as a PhD graduate in cognitive psychology at the University of Pittsburgh. Since joining the Academy, she has planned conferences spanning the medical and scientific topics of Drug Regulatory Decision Making, Cognitive Dysfunction in Multiple Sclerosis, Drug Discovery for Schizophrenia, and Innovating the Medical School Curriculum.
Ottavio Arancio, MD, PhD
Ottavio Arancio received his PhD and MD from the University of Pisa (Italy). From 1981 to 1986 he was in residency training in Neurology at the University of Verona (Italy). Arancio has held Faculty appointments at Columbia University, NYU School of Medicine, and at SUNY HSCB. In 2004 he became Faculty member of the Department of Pathology & Cell Biology and The Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University. Arancio is a cellular neurobiologist who has contributed to the characterization of the mechanisms of learning in both normal conditions and during neurodegenerative diseases. During the last ten years he has pioneered the field of mechanisms of synaptic dysfunction in Alzheimer's disease. Arancio's laboratory has focused primarily on events triggered by the amyloid protein. These studies, which have suggested new links between synaptic dysfunction and amyloid protein, are of a general relevance to the field of Alzheimer's disease both for understanding the etiopathogenesis of the disease and for developing therapies aiming to improve the cognitive symptoms. Arancio has been recently featured on bigthink.com.
Gilbert Di Paolo, PhD
Gilbert Di Paolo received a PhD in biology under the supervision of Gabriele Grenningloh from the University of Lausanne, Switzerland, in 1998. Following postdoctoral training at Yale University with Pietro De Camilli he obtained a faculty appointment at Columbia University Medical Center in 2005. He is currently an Assistant Professor in the Department of Pathology and Cell Biology and Taub Institute. His research is focused on the role of phosphoinositides and other phospholipids in the regulation of synaptic function. More recently, his laboratory has uncovered important links between lipid dysregulation and synaptic malfunction in mouse genetic models of Alzheimer's disease and Down syndrome.
Vahram Haroutunian, PhD
Vahram Haroutunian joined the faculty at The Mount Sinai School of Medicine in the summer of 1982 after completing postdoctoral training at Princeton University. He is a Professor of Psychiatry. Haroutunian came to Mount Sinai after completing a postdoctoral training program at Princeton concentrating on research in development and in aging. His research interests since joining the Mount Sinai faculty have centered on the neurobiology of Alzheimer's disease and schizophrenia. He directs the NIA-funded program project grant entitled Clinical and Biological Studies of Early Alzheimer's Disease and the Mount Sinai Aging, Dementia and Mental Illness Brain Bank. His research during the past few years has focused on the neurobiology of dementia and successful aging. His most recent research is directed at distinguishing between the neurobiological substrates of cognitive health and compromise in young-old and oldest-old persons as well as the role of modifiable cardiovascular risk factors in dementia prevention.
The primary aims of his mental illness related studies has been to understand the neurobiology of schizophrenia. Haroutunian and his colleagues described how abnormalities in myelin, the fatty coating around nerves that acts as an insulator and speed of signal transmission enhancer, are characteristic biological features of schizophrenia. This has spurred significant studies by his group and that of others into how information processing is degraded in the brain of persons with schizophrenia.
Barbara L. Hempstead, MD, PhD
Barbara Hempstead is a Professor of Medicine at Weill Cornell Medical College, and Co-Chief of the Division of Hematology and Medical Oncology. She obtained her MD and PhD from Washington University School of Medicine, and completed postdoctoral and clinical training at Weill Cornell Medical College. Her laboratory focuses on the biological actions of neurotrophins, specifically BDNF and NGF. These growth factors play critical roles in neuronal differentiation and survival, as well as in modulating synaptic transmission. Her laboratory first postulated a biological role for the precursor forms of neurotrophins (proneurotrophins), and subsequently has identified distinct roles for proneurotrophins in inducing neuronal death, and impairing synaptic transmission. Her research focuses on using genetic models to delineate the role of neurotrophins in establishing neuronal circuitry, modulating synaptic transmission, and acting as injury-induced cytokines. She is a prior Chair of the Gordon Conference on "Neurotrophic Factors."
Eric Klann, PhD
Eric Klann is Professor of Neural Science and Biology at New York University. He received his PhD from the Medical College of Virginia, did postdoctoral training at Baylor College of Medicine with David Sweatt, and previously held faculty positions at the Univeristy of Pittsburgh and Baylor College of Medicine. His lab uses a multidisciplinary approach, utilizing pharmacological, biochemical, molecular, genetic, electrophysiological, and behavioral techniques. His primary research interests are focused on the role of redox signaling and the mechanisms of translational control during long-lasting hippocampal synaptic plasticity and memory, and how these mechanisms are altered in mouse models of intellectual disability, autism, aging, and Alzheimer's disease. Klann is an Associate Editor for the Journal of Neuroscience, Molecular Brain, and Neurobiology of Learning and Memory, and serves on the Scientific Advisory Boards of the Foundation for Angelman Syndrome Therapeutics and the Fragile X Outcomes Measures Group of the National Institutes of Health.
Mark P. Mattson, PhD
After receiving his PhD from the University of Iowa, Mark Mattson completed a postdoctoral fellowship in Developmental Neuroscience at Colorado State University. He then joined the Sanders–Brown Center on Aging and the Department of Anatomy and Neurobiology at the University of Kentucky College of Medicine where he advanced to a Full Professor. In 2000, Mattson took the position of Chief of the Laboratory of Neurosciences at the National Institute on Aging in Baltimore, where he leads a multi-faceted research team that applies cutting-edge technologies in research aimed at understanding molecular and cellular mechanisms of brain aging and the pathogenesis of neurodegenerative disorders. He is also a Professor in the Department of Neuroscience at Johns Hopkins University School of Medicine.
Mattson's published findings are highly regarded: he has an 'h factor' of 130 and has been the most cited neuroscientist in the world during the past 15 years according to the ISI information database. He is Editor-in-Chief of NeuroMolecular Medicine and Ageing Research Reviews, and has been/is a Managing or Associate Editor of the Journal of Neuroscience, Trends in Neurosciences, the Journal of Neurochemistry, Neurobiology of Aging, and the Journal of Neuroscience Research.
Stephen M. Strittmatter, MD, PhD
Stephen M. Strittmatter earned his undergraduate degree from Harvard College, summa cum laude, in 1980. He completed MD and PhD training at Johns Hopkins in 1986 with mentorship from Solomon H. Snyder. He then moved to Massachusetts General Hospital for a medical internship and an Adult Neurology residency. While at Massachusetts General Hospital, he worked as a Research Fellow with Mark Fishman, exploring the molecular basis of axonal guidance. After a year as Fellow, he served briefly as an Assistant Professor at Harvard Medical School before moving to Yale University in 1993. He is currently holds the Vincent Coates Professorship of Neurology and founded the Yale Program in Cellular Neuroscience, Neurodegeneration and Repair. His research on axonal growth during development and regeneration has been recognized by honors from the Ameritec Foundation, the John Merck Fund, the Donaghue Foundation, the McKnight Foundation, the Jacob Javits Award of the NINDS and the American Academy of Neurology.
Grace E. Stutzmann, PhD
Grace Stutzmann received her PhD from the Center for Neural Science at New York University in 1999, working with Joseph LeDoux. Following this, she was a postdoctoral fellow with George Aghajanian at Yale University Medical School. A second postdoctoral research fellow position followed at UC Irvine, working with Ian Parker and Frank LaFerla in the Department of Neurobiology and Behavior and Institute for Brain Aging and Dementia. Currently, she is an Assistant Professor in Neuroscience at Rosalind Franklin University / The Chicago Medical School. Her research focuses on studying early pathogenic mechanisms contributing to AD pathogenesis and uncovering novel therapeutic strategies to prevent disease progression. Her primary techniques include live cell imaging, electrophysiology, and molecular approaches in mouse models of AD, with particular expertise in 2-photon calcium imaging and patch clamp recordings in brain slice preparations. Stutzmann is a member of the Society for Neuroscience and the Society of General Physiologists.
Lawrence P. Wennogle, PhD
Lawrence Wennogle received his PhD in Biochemistry from the University of Colorado, Boulder working under Howard Berg and Marvin Caruthers where he studied the structure of red blood cell membranes. He then completed two postdoctoral positions, one at the University of Colorado and the second at the Pasteur Institute in Paris, France, working under Jean-Pierre Changeux on the structure-function of the nicotinic acetylcholine receptor for Torpedo marmorata. With his broad expertise in drug discovery and the biochemical basis of disease, Wennogle supervises Intra-Cellular Therapies (ITI) development of small molecule therapeutics for neurodegenerative and neuropsychiatric disorders. ITI currently has a clinical candidate for schizophrenia undergoing phase 2 clinical trials. Wennogle is a Fellow of the New York Academy of Sciences and has co-authored over 50 scientific publications. He is a member of the New York Academy of Sciences, the American Association for the Advancement of Science, the American Chemical Society, Schizophrenia International Research and the Society for Neurosciences. He has adjunct appointments at Columbia University in the Department of Pharmacology and at University of Medicine and Dentistry, New Jersey in the Graduate School of Biomedical Sciences. His current focus is the development of novel therapeutics for cognitive dysfunction.
Kathleen McGowan is a freelance magazine writer specializing in science and medicine.
Vahram Haroutunian, Mount Sinai School of Medicine
Mark P. Mattson, National Institute on Aging
- Changes in the synapse in patients with Alzheimer's disease (AD) appear to affect all components of the synaptic machinery.
- Synaptic abnormalities are present in AD patients of all ages, even when other disease hallmarks such as plaques and tangles are less apparent.
- Caloric restriction reduces amyloid-β deposits in an animal model; intermittent fasting also protects against synaptic dysfunction.
- In animal and cell models, exercise promotes mechanisms that repair DNA damage.
- The insulin-sensitizing drug exendin-4 might slow cognitive decline.
The synapse in the oldest old
The synapse is the business end of a neuron, the place where its most important transactions take place. Presynaptically—the term refers to the cell producing a signal—neurotransmitters are packaged into vesicles that are transported to the cell membrane where they dock, fuse with the membrane, release their contents, and are recycled into new vesicles. On the presynaptic side, dysfunctions might involve any or all of these processes.
To examine changes in presynaptic function in brains affected by Alzheimer's disease, Vahram Haroutunian of the Mount Sinai School of Medicine conducted gene expression and messenger RNA (mRNA) analyses in samples of AD brains, focusing on the superior temporal gyrus (STG). Brains with vascular damage, inflammatory changes, or from patients with a life history of depression were excluded. To obtain a measure of synaptic integrity, Haroutunian's group compared mRNA and protein levels of several important synaptic players, including syntaxin-1, SNAP-25, complexin, synaptobrevin, and synaptophysin, in brains from controls and dementia patients. They found an overall 25% decrease in mRNA and protein levels of these gene products. The broad decline suggests the entire synapse was compromised in the disease. Protein and gene expression fall off with disease severity.
Microarray studies of brain samples reveal that dementia takes a different form in the brains of the "oldest old," those over the age of 85. The brains of people over that age who are equally demented as their younger counterparts have fewer plaques, less amyloid-β-40 and amyloid-β-42 (the two most common amyloid-β species) but synaptic pathology is comparable. In "young-old" patients under age 85, synaptic protein levels are the best correlate of dementia and neuropathology; in older patients, synaptic mRNA levels are more reflective of these changes. One possibility is that in these oldest patients, pathology is more localized, so that neurons projecting to the STG are less compromised than in younger patients.
Diet, exercise, and brain cell survival
Cognitive challenges, exercise, and reductions in dietary intake are powerful modulators of neuronal and synaptic vulnerability, perhaps because they activate adaptive stress mechanisms, suggested Mark Mattson of the National Institute of Aging in a review of studies from his group.
Most of the neurons that degenerate in Alzheimer's disease are glutamatergic, meaning that they are excitatory. The activity they induce in a healthy young brain puts mild stress on cells, encouraging the neurons to release neurotrophic factors that promote synaptic plasticity and cell survival. Presynaptic release of glutamate, when combined with growth factors, also promotes synaptogenesis. An excitatory imbalance may develop with aging that promotes amyloid-β aggregation and synaptic dysfunction; exercise and energy intake reduction may counteract these effects.
In experiments manipulating energy intake in a widely-used triple-transgenic AD mouse model that develops amyloid-β pathology, animals on a calorie-restricted diet of 30% normal rations for one year developed lower levels of amyloid-β than normally fed animals or those subjected to alternate-day fasting. However, synapses were preserved in the alternate-day-fasted animals despite their relatively high amyloid-β levels, suggesting that reducing amyloid-β is not required to prevent synaptic dysfunction. In another model, intermittent fasting protected young but not old animals against neurological deficits caused by an artificial stroke, a result that may be related to the more robust upregulation of brain-derived neurotrophic factor (BDNF) and other neurotrophins in younger brains.
Recent work establishes that BNDF upregulates a DNA repair enzyme in neurons in culture, and that exercise upregulates DNA repair mechanisms in vivo. "If you're using neurons, or exercising, you're increasing the neurons' ability to repair DNA damage," said Mattson. In another experiment, both calorie restriction and exercise increased the synapses in normal animals and in an animal model of diabetes, a condition that can accelerate the deterioration of cognitive function and synaptic plasticity. Exendin-4, prescribed as the diabetes drug Byetta for its ability to increase insulin sensitivity, also increases BDNF production and protects against neurodegeneration in AD models. It is being tested in early AD to slow cognitive decline.
Grace E. Stutzmann, Rosalind Franklin University/Chicago Medical School
Ottavio Arancio, Columbia University Medical Center
Barbara L. Hempstead, Weill Cornell Medical College
Gilbert Di Paolo, Columbia University
- Calcium signaling is disrupted in early Alzheimer's disease (AD), an effect that appears to be related to ryanodine receptor (RyR) function.
- Chronic treatment with RyR blockers selectively restored normal calcium signaling in AD mice.
- Increasing CREB phosphorylation via phosphodiesterase (PDE) inhibition might offer an effective AD therapeutic strategy.
- A novel PDE5 inhibitor restores normal synaptic function and memory following amyloid-β administration in slices and in vivo.
- Neurotrophins have potent effects on synaptic activity and neuronal survival.
- ProNGF, a neurotrophin precursor, may mediate cell death and dysfunction.
Manipulating calcium signals at the synapse
At the synapse, one of the most important and energy-intensive jobs is the effective regulation of ionic calcium inflow and efflux. This balance is compromised in Alzheimer's disease (AD), with related effects on signaling and plasticity. Disruptions in early calcium signaling—that is to say, calcium release from the endoplasmic reticulum through ryanodine receptor (RyR) and inositol triphosphate (IP3R) channels—were described by Grace Stutzmann of the Rosalind Franklin University and Chicago Medical School. In AD, these changes may contribute to synaptic loss. Evidence from slice preparations of AD mouse models suggests that alterations in calcium balance change neurotransmitter release and deplete vesicles, which could over time contribute to a breakdown in synaptic structure and function. Excitability increases in the postsynaptic neuron, and can be synergistically potentiated with caffeine, which activates RyR.
Data from experiments using postmortem human brains and from mouse models suggest that the RyR2 isoform is upregulated in the disease state. Manipulating RyR function and calcium signaling has different effects in normal and AD mouse models. Neurotransmission in normal animals does not appear to be affected by RyR blockade but does change in AD model animals, suggesting that this mechanism is engaged differently during baseline activity in normal and AD models.
Blocking RyR prevents long-term potentiation (LTP) and long-term depression (LTD), two contrasting cellular plasticity mechanisms associated with learning and memory. In a commonly used triple-transgenic AD mouse model, RyR blockade enhanced LTD and caused LTP to be converted into LTD. Chronic treatment with RyR blockers such as dantrolene normalized calcium signaling and plasticity in AD-model mice, suggesting that this receptor system might offer a suitable target for AD therapeutics. "We hope that by blocking Ry receptors at early presymptomatic stages, we could generate preventative therapeutic options," said Stutzmann.
The potential of CREB
Interfering directly with amyloid-β production is not the only way to restore synaptic plasticity in AD, and may not be the most effective therapeutic strategy, pointed out Ottavio Arancio of Columbia University Medical Center. He described work on targets downstream, in learning and memory mechanisms, particularly the transcription factor CREB (cAMP-response element binding protein). During induction of synaptic plasticity, CREB is phosphorylated, a process that is reduced by high levels of amyloid-β and tau. Conversely, the induction of two pathways that increase CREB phosphorylation via the inhibition of phosphodiesterase 4 reduce amyloid-β-related memory deficits and restore LTP in a transgenic AD mouse model. Encouragingly, memory rescue is also seen in older mice that had already developed significant neuropathology.
This observation suggests a new strategy for developing AD therapeutics; inhibiting one of two phosphodiesterases, PDE4 and PDE5, in order to enhance the effects of CREB-phosphorylating kinases. In mouse models, such PDE inhibitors re-establish normal CREB phosphorylation, alleviate memory loss, and restore LTP. No current PDE5 inhibitors are selective enough to be used in elderly populations, but Arancio described a novel PDE5-inhibiting compound with high potency and selectivity that rescues LTP in amyloid-β-treated hippocampal slices. His group is currently modifying the compound to improve druggability.
The promise and pitfalls of growth factors
Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have essential roles in synaptogenesis, modulating arborization and pruning of dendrites, and in synaptic plasticity, but the complex effects of these factors and their precursors are only partly understood. While neurotrophins promote neuronal survival and differentiation, the precursor form of nerve growth factor (NGF), may contribute to cell dysfunction or death, explained Barbara Hempstead of Weill Cornell Medical College.
In a variety of animal model systems and some SNP studies in humans, alterations in BDNF affect memory, anxiety, depression, and aggression. "Even modest increases of BDNF can have behavioral consequences," said Hempstead. BDNF is reduced in the brains of AD patients, and gene therapy delivery of BDNF in animal models improves memory and rescues neurons from lesion. A common genetic variant in the prodomain of BDNF in humans affects hippocampal memory and motor learning.
Gene therapy trials in humans are already investigating the therapeutic benefit of delivering nerve growth factor to the nucleus basalis in AD patients, but because of its invasive and technologically challenging nature, gene therapy may not be the best solution. An alternative approach would activate the TrkB receptor, which responds to neurotrophins, and various groups are now devising compounds to mimic the loop structures of BDNF.
At high concentrations, proneurotrophins, the precursor compounds of neurotrophins, paradoxically activate cell death mechanisms. ProNGF may also be expressed in neurodegenerative disease and even during mild cognitive impairment. Preventing proNGF actions may offer another therapeutic strategy; Hempstead suggested that given the complex protein structure, antibody-mediated blockade might be a good tactic to explore.
Stephen M. Strittmatter, Yale University School of Medicine
Eric Klann, New York University
Lawrence P. Wennogle, Intra-Cellular Therapeutics
- Low-abundance lipids are highly relevant to core processes in Alzheimer's disease (AD).
- Oligomers of amyloid-β bind to postsynaptic prion protein.
- Interactions between amyloid-β and prion protein may trigger changes in the phosphorylation and redistribution of NMDA receptors.
- Reactive oxygen species cause neuronal damage in AD.
- Overexpressing superoxide dismutase-2, which decreases superoxide, rescues deficits in memory and synaptic plasticity in AD model animals.
- A compound that blocks gamma-secretase activating protein reduces amyloid-β without affecting processing of the important protein Notch.
- PDE1 inhibitors could act as cognitive enhancers by increasing dopamine D1 receptor activity.
Lipids at the synapse
The third pathological hallmark of Alzheimer's disease, as noted by Alois Alzheimer in 1907, is lipid imbalance. Normal lipid function is essential to maintaining membrane properties, synaptic function and well-regulated signaling, but various lipids whose presence is important in the brain are dysregulated in AD and changes in their levels (both increases and decreases) can have powerful effects despite their low abundance. Cholesterol has received most of the attention, but metabolism of synaptojanin and phospholipase D is also altered in AD, said Gilbert Di Paolo of Columbia University. "The evidence is in the literature, phospholipases somehow have gone wild in AD," he said.
An unbiased "lipidomics" approach offers a way to identify previously unrecognized players in AD pathology. A comparison of lipid profiles of several mouse AD models and human AD brain samples, executed with HLPC and electrospray-ionization mass spectrometry, points to changes in diacylglycerol (DAG), the membrane component phosphatidylinositol 4,5 bisphosphate (Pi(4,5)p2 or PIP2), lysobisphosphatidic acid (LBPA), cholesterol esters, and other lipids.
The PIP2 products IP3 and DAG have a number of roles in neurons including stimulating the release of calcium from the ER, and regulating ion channels, cell adhesion processes, and exocytosis and endocytosis of synaptic vesicles. Experiments have suggested that amyloid-β42 leads to a decrease in PIP2 levels at the cell surface but also activates phospholipase C (PLC) metabolism of PIP2 to IP3 and DAG. To examine the effects of restoring the levels of PIP2 at the membrane, the team looked in a system where the conversion of PIP2 into PIP is absent because of the lack of the lipid phosphatase synaptojanin. Synaptojanin has been shown to be important in vesicle trafficking at the synapse. Slice experiments with a synaptojanin heterozygous knockout mouse show protection against PIP2-deficiency and LTP depression brought on by amyloid-β42, the most toxic version of the oligomer. Cognitive deficits are rescued when AD model mice are crossed with this knockout mouse, despite the fact that amyloid-β42 levels remain high, suggesting a downstream effect. Aβ42 perturbs dendritic spines, promoting "weak" signaling spines, and blocking synaptojanin also rescues this effect.
Amyloid and the prion connection
Plaques of amyloid-β may not be the most toxic forms of the protein; recently, attention has shifted to oligomers, which may be involved with cell surface binding in a way that leads to synaptic impairment. More specifically, said Stephen Strittmatter of Yale University School of Medicine, oligomers bind to dendrites in a way that suggests a receptor-like mechanism is at work. An unbiased genome-wide screen of cDNAs from mouse brain identified post-synaptic cellular prion protein (PrP-C), the normal version of the glycoprotein affected by prion disease. Several labs have confirmed that amyloid-β oligomers bind to prion protein.
The interaction of oligomeric assemblies with PrP activates Fyn kinase in a dose-dependent manner in transfected cells and in primary cortical neurons in culture. Fyn activation in turn phosphorylates the NR2B subunit of NMDA receptors, which are involved in learning and memory. NMDA receptor function and trafficking are affected by phosphorylation. When cells were preincubated with amyloid-β, NMDA receptor responses increased initially in response to calcium signaling, and subsequently were suppressed in a manner that correlates with surface expression of NMDA receptors. amyloid-β also drove NMDA receptors toward the surface.
PrP seems to be required for the amyloid-β related suppression of LTP, although not all groups have reached this same finding. Human AD brain extracts also inhibit LTP in vivo in a way mediated by PrP. Crossing AD model mice to PrP knockout animals rescued memory deficits, as did treating AD model mice with a high-dose PrP antibody.
The Roles of ROSs
Reactive oxygen species such as superoxide are another cellular stress that may be involved in the pathology of aging as well as AD and other neurodegenerative diseases. Reducing superoxide through the overexpression of superoxide dismutase 2 (SOD-2), can prevent memory deficits in one mouse model of AD, and rescue LTP impairments, said Eric Klann of New York University. SOD-2 overexpression also reduces superoxide levels in these mice, and reduces amyloid plaque formation by half.
Because injecting SOD-2 into the brain is not a likely therapeutic strategy, Klann's group explored MitoQ, a mitochondrial-targeted antioxidant. MitoQ prevented some deleterious effects of amyloid-β, such as increases in mitochondrial superoxide and LTP blockade. "This suggests that ongoing production of superoxide from mitochondria causes synaptic dysfunction, and implies that just by decreasing superoxide you can restore some degree of synaptic plasticity," said Klann.
Two more targets
Gamma-secretase, the enzyme that cleaves amyloid precursor protein into amyloid-β, is a challenging target because it is such a promiscuous protease with many physiologically important substrates. Intra-Cellular Therapeutics is pursuing an alternate strategy to interfere with amyloid-β production that involves targeting γ-secretase activating protein (GSAP), explained Lawrence Wennogle. GSAP apparently facilitates the interaction between γ-secretase and APP. Knocking down amyloid-β with GSAP siRNA does not affect cleavage of Notch, an essential protein. In collaboration with Rockefeller's Paul Greengard, Wennogle's group has identified a lead candidate that interferes with GSAP and does not affect Notch. "We've taken promiscuous γ-secretase and added specificity to this system," said Wennogle.
Another Intra-Cellular Therapeutics development program relevant to synaptic activity involves inhibitors for phosphodiesterase 1 (PDE1), which shuts down dopamine signaling in the brain. Inhibiting PDE1 might increase dopamine D1 receptor activity and have cognitive-enhancing effects. In an animal model, their lead compound enhanced all phases of memory, including acquisition, consolidation, and retrieval. It is currently in Phase 2 trials for cognitive enhancement in schizophrenia.
The synapse seems to be the place where dementia "happens," as AD brings on a wide range of marked changes in both animal models and human patients. As complex as this region is, it also offers a wide range of possible targets—a rich and promising region for AD therapeutics.
What protects the brains of the nondemented "oldest old"—those over 85?
Why do the brains of the "oldest old" show less plaque pathology than younger brains, even at the same level of AD symptom severity?
Do mild stresses like cognitive challenge or exercise induce an adaptive stress response?
Do environmental interventions such as restricting caloric intake or exercising promote neuronal resilience via neurotrophins?
Does early synaptic loss underlie cognitive deficits?
What role does proNGF play in neurodegeneration and cell death?
What anomalies in membrane lipid metabolism are caused by amyloid-β?
Does prion protein interact with other amyloid-β binding proteins?
Is prion protein necessary for the LTP-suppressing affects of amyloid-β?
What is the precise molecular mechanism by which synaptojanin inhibition prevents LTP impairment?
Can reducing reactive oxygen species in the aged brain restore synaptic plasticity?