Disruption of cholinergic neurotransmission contributes to the memory impairment that characterizes Alzheimer disease (AD). Since the amyloid cascade hypothesis of AD pathogenesis postulates that amyloid β (Aβ) peptide accumulation in critical brain regions also contributes to memory impairment, we assessed cholinergic function in transgenic mice where the human Aβ peptide is overexpressed. We first measured hippocampal acetylcholine (ACh) release in young, freely moving PDAPP mice, a well-characterized transgenic mouse model of AD, and found marked Aβ-dependent alterations in both basal and evoked ACh release compared with WT controls. We also found that Aβ could directly interact with the high-affinity choline transporter which may impair steady-state and on-demand ACh release. Treatment of PDAPP mice with the anti-Aβ antibody m266 rapidly and completely restored hippocampal ACh release and high-affinity choline uptake while greatly reducing impaired habituation learning that is characteristic of these mice. Thus, soluble “cholinotoxic” species of the Aβ peptide can directly impair cholinergic neurotransmission in PDAPP mice leading to memory impairment in the absence of overt neurodegeneration. Treatment with certain anti-Aβ antibodies may therefore rapidly reverse this cholinergic dysfunction and relieve memory deficits associated with early AD.
Kelly R. Bales, Eleni T. Tzavara, Su Wu, Mark R. Wade, Frank P. Bymaster, Steven M. Paul, George G. Nomikos
Accumulation and aggregation of amyloid β peptide 1–42 (Aβ42) in the brain has been hypothesized as triggering a pathological cascade that causes Alzheimer disease (AD). To determine whether selective targeting of Aβ42 versus Aβ40 or total Aβ is an effective way to prevent or treat AD, we compared the effects of passive immunization with an anti-Aβ42 mAb, an anti-Aβ40 mAb, and multiple Aβ1–16 mAbs. We established in vivo binding selectivity of the anti-Aβ42 and anti-Aβ40 mAbs using novel TgBRI-Aβ mice. We then conducted a prevention study in which the anti-Aβ mAbs were administered to young Tg2576 mice, which have no significant Aβ deposition, and therapeutic studies in which mAbs were administered to Tg2576 or CRND8 mice with modest levels of preexisting Aβ deposits. Anti-Aβ42, anti-Aβ40, and anti-Aβ1–16 mAbs attenuated plaque deposition in the prevention study. In contrast, anti-Aβ42 and anti-Aβ40 mAbs were less effective in attenuating Aβ deposition in the therapeutic studies and were not effective in clearing diffuse plaques following direct injection into the cortex. These data suggest that selective targeting of Aβ42 or Aβ40 may be an effective strategy to prevent amyloid deposition, but may have limited benefit in a therapeutic setting.
Yona Levites, Pritam Das, Robert W. Price, Marjorie J. Rochette, Lisa A. Kostura, Eileen M. McGowan, Michael P. Murphy, Todd E. Golde
Degeneration of peripheral motor axons is a common feature of several debilitating diseases including complicated forms of hereditary spastic paraplegia. One such form is caused by loss of the mitochondrial energy-dependent protease paraplegin. Paraplegin-deficient mice display a progressive degeneration in several axonal tracts, characterized by the accumulation of morphological abnormal mitochondria. We show that adenoassociated virus–mediated (AAV-mediated) intramuscular delivery of paraplegin halted the progression of neuropathological changes and rescued mitochondrial morphology in the peripheral nerves of paraplegin-deficient mice. One single injection before onset of symptoms improved the motor performance of paraplegin-deficient mice for up to 10 months, indicating that the peripheral neuropathy contributes to the clinical phenotype. This study provides a proof of principle that gene transfer may be an effective therapeutic option for patients with paraplegin deficiency and demonstrates that AAV vectors can be successfully employed for retrograde delivery of an intracellular protein to spinal motor neurons, opening new perspectives for several hereditary axonal neuropathies of the peripheral nerves.
Marinella Pirozzi, Angelo Quattrini, Gennaro Andolfi, Giorgia Dina, Maria Chiara Malaguti, Alberto Auricchio, Elena I. Rugarli
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases characterized by progressive weakness and spasticity of the lower limbs. Dominant mutations in the human SPG4 gene, encoding spastin, are responsible for the most frequent form of HSP. Spastin is an ATPase that binds microtubules and localizes to the spindle pole and distal axon in mammalian cell lines. Furthermore, its Drosophila homolog, Drosophila spastin (Dspastin), has been recently shown to regulate microtubule stability and synaptic function at the Drosophila larval neuromuscular junction. Here we report the generation of a spastin-linked HSP animal model and show that in Drosophila, neural knockdown of Dspastin and, conversely, neural overexpression of Dspastin containing a conserved pathogenic mutation both recapitulate some phenotypic aspects of the human disease, including adult onset, locomotor impairment, and neurodegeneration. At the subcellular level, neuronal expression of both Dspastin RNA interference and mutant Dspastin cause an excessive stabilization of microtubules in the neuromuscular junction synapse. In addition, we provide evidence that administration of the microtubule targeting drug vinblastine significantly attenuates these phenotypes in vivo. Our findings demonstrate that loss of spastin function elicits HSP-like phenotypes in Drosophila, provide novel insights into the molecular mechanism of spastin mutations, and raise the possibility that therapy with Vinca alkaloids may be efficacious in spastin-associated HSP and other disorders related to microtubule dysfunction.
Genny Orso, Andrea Martinuzzi, Maria Giovanna Rossetto, Elena Sartori, Mel Feany, Andrea Daga
Accumulation of amyloid-β (Aβ) within extracellular spaces of the brain is a hallmark of Alzheimer disease (AD). In sporadic, late-onset AD, there is little evidence for increased Aβ production, suggesting that decreased elimination from the brain may contribute to elevated levels of Aβ and plaque formation. Efflux transport of Aβ across the blood-brain barrier (BBB) contributes to Aβ removal from the brain. P-glycoprotein (Pgp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. In Pgp-null mice, we show that [125I]Aβ40 and [125I]Aβ42 microinjected into the CNS clear at half the rate that they do in WT mice. When amyloid precursor protein–transgenic (APP-transgenic) mice were administered a Pgp inhibitor, Aβ levels within the brain interstitial fluid significantly increased within hours of treatment. Furthermore, APP-transgenic, Pgp-null mice had increased levels of brain Aβ and enhanced Aβ deposition compared with APP-transgenic, Pgp WT mice. These data establish a direct link between Pgp and Aβ metabolism in vivo and suggest that Pgp activity at the BBB could affect risk for developing AD as well as provide a novel diagnostic and therapeutic target.
John R. Cirrito, Rashid Deane, Anne M. Fagan, Michael L. Spinner, Maia Parsadanian, Mary Beth Finn, Hong Jiang, Julie L. Prior, Abhay Sagare, Kelly R. Bales, Steven M. Paul, Berislav V. Zlokovic, David Piwnica-Worms, David M. Holtzman
Neurologic impairment in HIV-1–associated dementia (HAD) and other neuroinflammatory diseases correlates with injury to dendrites and synapses, but how such injury occurs is not known. We hypothesized that neuroinflammation makes dendrites susceptible to excitotoxic injury following synaptic activity. We report that platelet-activating factor, an inflammatory phospholipid that mediates synaptic plasticity and neurotoxicity and is dramatically elevated in the brain during HAD, promotes dendrite injury following elevated synaptic activity and can replicate HIV-1–associated dendritic pathology. In hippocampal slices exposed to a stable platelet-activating factor analogue, tetanic stimulation that normally induces long-term synaptic potentiation instead promoted development of calcium- and caspase-dependent dendritic beading. Chemical preconditioning with diazoxide, a mitochondrial ATP-sensitive potassium channel agonist, prevented dendritic beading and restored long-term potentiation. In contrast to models invoking excessive glutamate release, these results suggest that physiologic synaptic activity may trigger excitotoxic dendritic injury during chronic neuroinflammation. Furthermore, preconditioning may represent a novel therapeutic strategy for preventing excitotoxic injury while preserving physiologic plasticity.
Matthew J. Bellizzi, Shao-Ming Lu, Eliezer Masliah, Harris A. Gelbard
The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, Gi/o proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis.
Wen Jiang, Yun Zhang, Lan Xiao, Jamie Van Cleemput, Shao-Ping Ji, Guang Bai, Xia Zhang
Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.
Adam I. Kaplin, Deepa M. Deshpande, Erick Scott, Chitra Krishnan, Jessica S. Carmen, Irina Shats, Tara Martinez, Jennifer Drummond, Sonny Dike, Mikhail Pletnikov, Sanjay C. Keswani, Timothy H. Moran, Carlos A. Pardo, Peter A. Calabresi, Douglas A. Kerr
Deficiency in docosahexaenoic acid (DHA), a brain-essential omega-3 fatty acid, is associated with cognitive decline. Here we report that, in cytokine-stressed human neural cells, DHA attenuates amyloid-β (Aβ) secretion, an effect accompanied by the formation of NPD1, a novel, DHA-derived 10,17S-docosatriene. DHA and NPD1 were reduced in Alzheimer disease (AD) hippocampal cornu ammonis region 1, but not in the thalamus or occipital lobes from the same brains. The expression of key enzymes in NPD1 biosynthesis, cytosolic phospholipase A2 and 15-lipoxygenase, was altered in AD hippocampus. NPD1 repressed Aβ42-triggered activation of proinflammatory genes while upregulating the antiapoptotic genes encoding Bcl-2, Bcl-xl, and Bfl-1(A1). Soluble amyloid precursor protein-α stimulated NPD1 biosynthesis from DHA. These results indicate that NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Aβ42-induced neurotoxicity.
Walter J. Lukiw, Jian-Guo Cui, Victor L. Marcheselli, Merete Bodker, Anja Botkjaer, Katherine Gotlinger, Charles N. Serhan, Nicolas G. Bazan
Amyloid β-peptide (Aβ) appears to play a key pathogenic role in Alzheimer disease (AD). Immune therapy in mouse models of AD via Aβ immunization or passive administration of Aβ antibodies markedly reduces Aβ levels and reverses behavioral impairment. However, a human trial of Aβ immunization led to meningoencephalitis in some patients and was discontinued. Here we show that nasal vaccination with a proteosome-based adjuvant that is well tolerated in humans plus glatiramer acetate, an FDA-approved synthetic copolymer used to treat multiple sclerosis, potently decreases Aβ plaques in an AD mouse model. This effect did not require the presence of antibody, as it was observed in B cell–deficient (Ig μ–null) mice. Vaccinated animals developed activated microglia that colocalized with Aβ fibrils, and the extent of microglial activation correlated strongly with the decrease in Aβ fibrils. Activation of microglia and clearing of Aβ occurred with the adjuvant alone, although to a lesser degree. Our results identify a novel approach to immune therapy for AD that involves clearing of Aβ through the utilization of compounds that have been safely tested on or are currently in use in humans.
Dan Frenkel, Ruth Maron, David S. Burt, Howard L. Weiner
The abnormal accumulation of amyloid β-peptide (Aβ) in the form of senile (or amyloid) plaques is one of the main characteristics of Alzheimer disease (AD). Both cholesterol and Cu2+ have been implicated in AD pathogenesis and plaque formation. Aβ binds Cu2+ with very high affinity, forming a redox-active complex that catalyzes H2O2 production from O2 and cholesterol. Here we show that Aβ:Cu2+ complexes oxidize cholesterol selectively at the C-3 hydroxyl group, catalytically producing 4-cholesten-3-one and therefore mimicking the activity of cholesterol oxidase, which is implicated in cardiovascular disease. Aβ toxicity in neuronal cultures correlated with this activity, which was inhibited by Cu2+ chelators including clioquinol. Cell death induced by staurosporine or H2O2 did not elevate 4-cholesten-3-one levels. Brain tissue from AD subjects had 98% more 4-cholesten-3-one than tissue from age-matched control subjects. We observed a similar increase in the brains of Tg2576 transgenic mice compared with nontransgenic littermates; the increase was inhibited by in vivo treatment with clioquinol, which suggests that brain Aβ accumulation elevates 4-cholesten-3-one levels in AD. Cu2+-mediated oxidation of cholesterol may be a pathogenic mechanism common to atherosclerosis and AD.
Luigi Puglielli, Avi L. Friedlich, Kenneth D.R. Setchell, Seiichi Nagano, Carlos Opazo, Robert A. Cherny, Kevin J. Barnham, John D. Wade, Simon Melov, Dora M. Kovacs, Ashley I. Bush
Cold hyperalgesia is a well-documented symptom of inflammatory and neuropathic pain; however, the underlying mechanisms of this enhanced sensitivity to cold are poorly understood. A subset of transient receptor potential (TRP) channels mediates thermosensation and is expressed in sensory tissues, such as nociceptors and skin. Here we report that the pharmacological blockade of TRPA1 in primary sensory neurons reversed cold hyperalgesia caused by inflammation and nerve injury. Inflammation and nerve injury increased TRPA1, but not TRPM8, expression in tyrosine kinase A–expressing dorsal root ganglion (DRG) neurons. Intrathecal administration of anti–nerve growth factor (anti-NGF), p38 MAPK inhibitor, or TRPA1 antisense oligodeoxynucleotide decreased the induction of TRPA1 and suppressed inflammation- and nerve injury–induced cold hyperalgesia. Conversely, intrathecal injection of NGF, but not glial cell line–derived neurotrophic factor, increased TRPA1 in DRG neurons through the p38 MAPK pathway. Together, these results demonstrate that an NGF-induced TRPA1 increase in sensory neurons via p38 activation is necessary for cold hyperalgesia. Thus, blocking TRPA1 in sensory neurons might provide a fruitful strategy for treating cold hyperalgesia caused by inflammation and nerve damage.
Koichi Obata, Hirokazu Katsura, Toshiyuki Mizushima, Hiroki Yamanaka, Kimiko Kobayashi, Yi Dai, Tetsuo Fukuoka, Atsushi Tokunaga, Makoto Tominaga, Koichi Noguchi
G-CSF is a potent hematopoietic factor that enhances survival and drives differentiation of myeloid lineage cells, resulting in the generation of neutrophilic granulocytes. Here, we show that G-CSF passes the intact blood-brain barrier and reduces infarct volume in 2 different rat models of acute stroke. G-CSF displays strong antiapoptotic activity in mature neurons and activates multiple cell survival pathways. Both G-CSF and its receptor are widely expressed by neurons in the CNS, and their expression is induced by ischemia, which suggests an autocrine protective signaling mechanism. Surprisingly, the G-CSF receptor was also expressed by adult neural stem cells, and G-CSF induced neuronal differentiation in vitro. G-CSF markedly improved long-term behavioral outcome after cortical ischemia, while stimulating neural progenitor response in vivo, providing a link to functional recovery. Thus, G-CSF is an endogenous ligand in the CNS that has a dual activity beneficial both in counteracting acute neuronal degeneration and contributing to long-term plasticity after cerebral ischemia. We therefore propose G-CSF as a potential new drug for stroke and neurodegenerative diseases.
Armin Schneider, Carola Krüger, Tobias Steigleder, Daniela Weber, Claudia Pitzer, Rico Laage, Jaroslaw Aronowski, Martin H. Maurer, Nikolaus Gassler, Walter Mier, Martin Hasselblatt, Rainer Kollmar, Stefan Schwab, Clemens Sommer, Alfred Bach, Hans-Georg Kuhn, Wolf-Rüdiger Schäbitz
Williams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS.
Andreas Meyer-Lindenberg, Carolyn B. Mervis, Deepak Sarpal, Paul Koch, Sonya Steele, Philip Kohn, Stefano Marenco, Colleen A. Morris, Saumitra Das, Shane Kippenhan, Venkata S. Mattay, Daniel R. Weinberger, Karen Faith Berman
MS is a chronic inflammatory and demyelinating disease of the CNS with as yet unknown etiology. A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF). To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins. The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes. In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells. Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors. Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins. Also, CD8+ T cell responses to latent EBV proteins were higher in MS patients than in controls. In summary, these findings demonstrate an increased immune response to EBV in MS patients, which suggests that the virus plays an important role in the pathogenesis of disease.
Sabine Cepok, Dun Zhou, Rajneesh Srivastava, Stefan Nessler, Susanne Stei, Konrad Büssow, Norbert Sommer, Bernhard Hemmer
Blockade of prostaglandin (PG) production by COX inhibitors is the treatment of choice for inflammatory pain but is also prone to severe side effects. Identification of signaling elements downstream of COX inhibition, particularly of PG receptor subtypes responsible for pain sensitization (hyperalgesia), provides a strategy for better-tolerated analgesics. Here, we have identified PGE2 receptors of the EP2 receptor subtype as key signaling elements in spinal inflammatory hyperalgesia. Mice deficient in EP2 receptors (EP2–/– mice) completely lack spinal PGE2-evoked hyperalgesia. After a peripheral inflammatory stimulus, EP2–/– mice exhibit only short-lasting peripheral hyperalgesia but lack a second sustained hyperalgesic phase of spinal origin. Electrophysiological recordings identify diminished synaptic inhibition of excitatory dorsal horn neurons as the dominant source of EP2 receptor–dependent hyperalgesia. Our results thus demonstrate that inflammatory hyperalgesia can be treated by targeting of a single PG receptor subtype and provide a rational basis for new analgesic strategies going beyond COX inhibition.
Heiko Reinold, Seifollah Ahmadi, Ulrike B. Depner, Beate Layh, Cornelia Heindl, May Hamza, Andreas Pahl, Kay Brune, Shuh Narumiya, Ulrike Müller, Hanns Ulrich Zeilhofer
Essential tremor is the most common movement disorder and has an unknown etiology. Here we report that γ-aminobutyric acidA (GABAA) receptor α1–/– mice exhibit postural and kinetic tremor and motor incoordination that is characteristic of essential tremor disease. We tested mice with essential-like tremor using current drug therapies that alleviate symptoms in essential tremor patients (primidone, propranolol, and gabapentin) and several candidates hypothesized to reduce tremor, including ethanol; the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801; the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA); the GABAA receptor modulators diazepam, allopregnanolone, and Ro15-4513; and the L-type Ca2+ channel antagonist nitrendipine. Primidone, propranolol, and gabapentin reduced the amplitude (power) of the pathologic tremor. Nonsedative doses of ethanol eliminated tremor in mice. Diazepam, allopregnanolone, Ro15-4513, and nitrendipine had no effect or enhanced tremor, whereas MK-801 and CCPA reduced tremor. To understand the etiology of tremor in these mice, we studied the electrophysiological properties of cerebellar Purkinje cells. Cerebellar Purkinje cells in GABAA receptor α1–/– mice exhibited a profound loss of all responses to synaptic or exogenous GABA, but no differences in abundance, gross morphology, or spontaneous synaptic activity were observed. This genetic animal model elucidates a mechanism of GABAergic dysfunction in the major motor pathway and potential targets for pharmacotherapy of essential tremor.
Jason E. Kralic, Hugh E. Criswell, Jessica L. Osterman, Todd K. O’Buckley, Mary E. Wilkie, Douglas B. Matthews, Kristin Hamre, George R. Breese, Gregg E. Homanics, A. Leslie Morrow
Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, the role of these proteins in normal CNS development is unknown. Here, we used a conditional gene-targeting approach to inactivate Atrx, specifically in the forebrain of mice. Loss of ATRX protein caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal “birthdating” confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Moreover, cortical progenitors isolated from Atrx-null mice undergo enhanced apoptosis upon differentiation. Taken together, our results indicate that ATRX is a critical mediator of cell survival during early neuronal differentiation. Thus, increased neuronal loss may contribute to the severe mental retardation observed in human patients.
Nathalie G. Bérubé, Marie Mangelsdorf, Magdalena Jagla, Jackie Vanderluit, David Garrick, Richard J. Gibbons, Douglas R. Higgs, Ruth S. Slack, David J. Picketts
Neuritic plaques are a defining feature of Alzheimer disease (AD) pathology. These structures are composed of extracellular accumulations of amyloid-β peptide (Aβ) and other plaque-associated proteins, surrounded by large, swollen axons and dendrites (dystrophic neurites) and activated glia. Dystrophic neurites are thought to disrupt neuronal function, but whether this damage is static, dynamic, or reversible is unknown. To address this, we monitored neuritic plaques in the brains of living PDAPP;Thy-1:YFP transgenic mice, a model that develops AD-like pathology and also stably expresses yellow fluorescent protein (YFP) in a subset of neurons in the brain. Using multiphoton microscopy, we observed and monitored amyloid through cranial windows in PDAPP;Thy-1:YFP double-transgenic mice using the in vivo amyloid-imaging fluorophore methoxy-X04, and individual YFP-labeled dystrophic neurites by their inherent fluorescence. In vivo studies using this system suggest that amyloid-associated dystrophic neurites are relatively stable structures in PDAPP;Thy-1:YFP transgenic mice over several days. However, a significant reduction in the number and size of dystrophic neurites was seen 3 days after Aβ deposits were cleared by anti-Aβ antibody treatment. This analysis suggests that ongoing axonal and dendritic damage is secondary to Aβ and is, in part, rapidly reversible.
Robert P. Brendza, Brian J. Bacskai, John R. Cirrito, Kelly A. Simmons, Jesse M. Skoch, William E. Klunk, Chester A. Mathis, Kelly R. Bales, Steven M. Paul, Bradley T. Hyman, David M. Holtzman
Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid β-peptide 1–42 (Aβ42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element–binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Aβ. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Aβ42 levels.
Bing Gong, Ottavio V. Vitolo, Fabrizio Trinchese, Shumin Liu, Michael Shelanski, Ottavio Arancio