Alzheimer Disease: LaFerla FM

Caccamo A, Fisher A, LaFerla FM. · Department of Neurobiology, University of California, Irvine, Irvine, CA 92697, USA. · Curr Alzheimer Res. · Pubmed #19355845 No free full text.

Abstract: Cholinergic deficit is a cardinal feature of Alzheimer's disease, and cholinesterase inhibitors represent one of the most prominent means of mitigating this dysfunction. Cholinesterase inhibitors provide mild symptomatic relief, although they lose their efficacy over time most likely because they are not disease-modifying agents. An alternative strategy for restoring cholinergic function and attenuating the cognitive decline involves acting on the receptors on which acetylcholine acts. Stimulation of muscarinic acetylcholine receptors and in particular the M1 subtype has been shown to have a beneficial effect in restoring cognition in patients with Alzheimer's disease and in attenuating Abeta and tau pathology in different animal models. In this review, we discuss the role of M1 agonists as a potential disease-modifying therapy for Alzheimer's disease.

Morrissette DA, Parachikova A, Green KN, LaFerla FM. · Department of Neurobiology and Behavior and Institute for Brain Aging and Dementia, University of California, Irvine, California 92697-4545, USA. · J Biol Chem. · Pubmed #18948253 No free full text.

Abstract: During the past 2 decades, the elucidation of susceptibility and causative genes for Alzheimer disease as well as proteins involved in the pathogenic process has greatly facilitated the development of genetically altered mouse models. These models have played a major role in defining critical disease-related mechanisms and in evaluating novel therapeutic approaches, with many treatments currently in clinical trial owing their origins to studies initially performed in mice. This review discusses the utility of transgenic mice as a research tool and their contributions to our understanding of Alzheimer disease.

Green KN, LaFerla FM. · Department of Neurobiology and Behavior and Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, CA 92697-4545, USA. · Neuron. · Pubmed #18667147 No free full text.

Abstract: Recent developments point to a critical role for calcium dysregulation in the pathogenesis of Alzheimer's disease. A novel calcium-conducting channel called CALHM1 is genetically linked to the disorder and modulates Abeta production. Calcium homeostasis has also been shown to be perturbed in dendritic spines adjacent to amyloid plaques. Finally, new studies have elucidated the role by which presenilins modulate calcium signaling, including effects on SERCA2b and gating of the IP(3) receptor, and lead to Abeta production.

LaFerla FM, Green KN, Oddo S. · Department of Neurobiology and Behaviour, and Institute for Brain Aging and Dementia, University of California, Irvine, California 92697-4545, USA. · Nat Rev Neurosci. · Pubmed #17551515 No free full text.

Abstract: The primal role that the amyloid-beta (Abeta) peptide has in the development of Alzheimer's disease is now almost universally accepted. It is also well recognized that Abeta exists in multiple assembly states, which have different physiological or pathophysiological effects. Although the classical view is that Abeta is deposited extracellularly, emerging evidence from transgenic mice and human patients indicates that this peptide can also accumulate intraneuronally, which may contribute to disease progression.

Giménez-Llort L, Blázquez G, Cañete T, Johansson B, Oddo S, Tobeña A, LaFerla FM, Fernández-Teruel A. · Medical Psychology Unit, Department of Psychiatry and Forensic Medicine, School of Medicine, Institute of Neuroscience, Autonomous University of Barcelona, 08193 Bellaterra, Barcelona, Spain. · Neurosci Biobehav Rev. · Pubmed #17055579 No free full text.

Abstract: The amyloid Abeta-peptide (Abeta) is suspected to play a critical role in the cascade leading to AD as the pathogen that causes neuronal and synaptic dysfunction and, eventually, cell death. Therefore, it has been the subject of a huge number of clinical and basic research studies on this disease. Abeta is typically found aggregated in extracellular amyloid plaques that occur in specific brain regions enriched in nAChRs in Alzheimer's disease (AD) and Down syndrome (DS) brains. Advances in the genetics of its familiar and sporadic forms, together with those in gene transfer technology, have provided valuable animal models that complement the traditional cholinergic approaches, although modeling the neuronal and behavioral deficits of AD in these models has been challenging. More recently, emerging evidence indicates that intraneuronal accumulation of Abeta may also contribute to the cascade of neurodegenerative events and strongly suggest that it is an early, pathological biomarker for the onset of AD and associated cognitive and other behavioral deficits. The present review covers these studies in humans, in in vitro and in transgenic models, also providing more evidence that adult 3xTg-AD mice harboring PS1M146V, APPSwe, tauP301L transgenes, and mimicking many critical hallmarks of AD, show cognitive deficits and other behavioral alterations at ages when overt neuropathology is not yet observed, but when intraneuronal Abeta, synaptic and cholinergic deficits can already be described.

Oddo S, LaFerla FM. · Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, CA 92697-4545, USA. · J Physiol Paris. · Pubmed #16448808 No free full text.

Abstract: The two hallmark lesions of Alzheimer's disease (AD) are extracellular amyloid plaques, mainly formed by a small peptide called amyloid-beta (Abeta), and neurofibrillary tangles, which are intracellular inclusions formed by aggregates of hyperphosphorylated tau protein. One of the major neurochemical features of AD is the marked reduction of nicotinic acetylcholine receptors in disease-relevant brain regions such as the cerebral cortex and hippocampus. This loss is further compounded by the loss of cholinergic cells, which contributes to the cognitive dysfunction. This observation has had a major impact on therapeutic treatments, as efforts to restore cholinergic function such as the administration of acetylcholinesterase inhibitors have been, until recently, the major treatment options available for AD. Understanding the relationship of these hallmark lesions with the plethora of other changes that occur in the AD brain has proven to be a difficult challenge to resolve. The utilization of transgenic mouse models, that recapitulate one or more neuropathological and neurochemical features of the AD brain is providing some inroads, as they offer a means to gain mechanistic insights into the disease process in an in vivo setting. In this review, we consider the role of nicotinic acetylcholine receptors in transgenic models and in AD.

Smith IF, Green KN, LaFerla FM. · Department of Neurobiology and Behavior, University of California, 1109 Gillespie Neuroscience Building, Irvine CA 92697-4545, USA. · Cell Calcium. · Pubmed #16125228 No free full text.

Abstract: Alzheimer's disease is a progressive and irreversible neurodegenerative disorder that leads to cognitive, memory and behavioural impairments. Two decades of research have implicated disturbances of intracellular calcium homeostasis as playing a proximal pathological role in the neurodegeneration associated with Alzheimer's disease. A large preponderance of evidence has been gained from the use of a diverse range of cell lines. Whilst useful in understanding the principal mechanism of neurotoxicity associated with Alzheimer's disease, technical differences, such as cell type or even the form of amyloid-beta used often underlie conflicting results. In this review, we discuss recent contributions that transgenic technology has brought to this field. For example, the triple transgenic mouse model of Alzheimer's disease has implicated intraneuronal accumulation of the amyloid-beta peptide as an initiating factor in synaptic dysfunction and behavioural deficits. Importantly, this synaptic dysfunction occurs prior to cell loss or extracellular amyloid plaque accumulation. The cause of synaptic dysfunction is unknown but it is likely that amyloid-beta and its ability to disrupt intracellular calcium homeostasis plays a key role in this process.

Tseng BP, Kitazawa M, LaFerla FM. · Laboratory of Molecular Neuropathogenesis, Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4545, USA. · Curr Alzheimer Res. · Pubmed #15975052 No free full text.

Abstract: The amyloid beta-peptide (Abeta) plays an early and critical role in the pathogenic cascade leading to Alzheimer's disease (AD). Abeta is typically found in extracellular amyloid plaques that occur in specific brain regions in the AD and Down syndrome brain. Mounting evidence, however, indicates that intraneuronal accumulation of this peptide may also contribute to the cascade of neurodegenerative events that occur in AD and Down syndrome. A pathogenic role for intracellular Abeta is not without precedent, as it is known to be an early and integral component of the human muscle disorder inclusion body myositis (IBM). Therefore, it is plausible that intracellular Abeta may likewise induce cytopathic effects in the CNS, causing neuronal and synaptic dysfunction and perhaps even neuronal loss. Here we review recent evidence supporting a pathogenic role for intracellular Abeta in AD, Down syndrome, and IBM.

LaFerla FM, Oddo S. · Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4545, USA. · Trends Mol Med. · Pubmed #15823755 No free full text.

Abstract: Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by two hallmark lesions: extracellular amyloid plaques and neurofibrillary tangles. The role that these lesions have in the pathogenesis of AD has proven difficult to unravel, in part because of unanticipated challenges of reproducing both pathologic hallmarks in transgenic mice. Recent advances in recapitulating both plaques and tangles in the brains of transgenic mice are leading to novel insights into their role in the degenerative process, including their impact on synaptic activity and plasticity. Transgenic mice that harbor both neuropathological lesions are also facilitating the elucidation of the relationship of these proteinaceous aggregates to one another and providing a crucial in vivo system for developing and evaluating therapies.

Kitazawa M, Yamasaki TR, LaFerla FM. · Laboratory of Molecular Neuropathogenesis, Department of Neurobiology and Behavior, University of California, Irvine, 92697-4545, USA. · Ann N Y Acad Sci. · Pubmed #15681802 No free full text.

Abstract: Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD), consisting of the activation of both microglia and astrocytes. Activated microglia and reactive astrocytes are found in and around extraneuronal amyloid-beta plaques and are thought to facilitate the clearance of these deposits from the brain parenchyma. However, mounting evidence indicates that chronic activation of microglia, presumably via the secretion of cytokines and reactive molecules, may exacerbate plaque pathology as well as enhance the hyperphosphorylation of tau and the subsequent development of neurofibrillary tangles. Thus, suppression of microglial activity in AD brain has been considered as a potential treatment of AD and may slow the disease progression. Along these lines, anti-inflammatory drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), lessen the effects of AD pathology. In this review, we discuss the molecular mechanism of inflammatory responses in AD brain as well as animal models, and current therapies using NSAIDs, antioxidants, and immunotherapy as neuroprotective strategies for AD.

LaFerla FM. · Laboratory of Molecular Neuropathogenesis, Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, California 92697, USA. · Nat Rev Neurosci. · Pubmed #12415294 No free full text.

This publication has no abstract.

McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, Das P, Golde TE, LaFerla FM, Oddo S, Blesch A, Tansey MG. · Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9040, USA. · Neurobiol Dis. · Pubmed #19320056 No free full text.

Abstract: Microglial activation and overproduction of inflammatory mediators in the central nervous system (CNS) have been implicated in Alzheimer's disease (AD). Elevated levels of the pro-inflammatory cytokine tumor necrosis factor (TNF) have been reported in serum and post-mortem brains of patients with AD, but its role in progression of AD is unclear. Using novel engineered dominant negative TNF inhibitors (DN-TNFs) selective for soluble TNF (solTNF), we investigated whether blocking TNF signaling with chronic infusion of the recombinant DN-TNF XENP345 or a single injection of a lentivirus encoding DN-TNF prevented the acceleration of AD-like pathology induced by chronic systemic inflammation in 3xTgAD mice. We found that chronic inhibition of solTNF signaling with either approach decreased the LPS-induced accumulation of 6E10-immunoreactive protein in hippocampus, cortex, and amygdala. Immunohistological and biochemical approaches using a C-terminal APP antibody indicated that a major fraction of the accumulated protein was likely to be C-terminal APP fragments (beta-CTF) while a minor fraction consisted of Av40 and 42. Genetic inactivation of TNFR1-mediated TNF signaling in 3xTgAD mice yielded similar results. Taken together, our studies indicate that soluble TNF is a critical mediator of the effects of neuroinflammation on early (pre-plaque) pathology in 3xTgAD mice. Targeted inhibition of solTNF in the CNS may slow the appearance of amyloid-associated pathology, cognitive deficits, and potentially the progressive loss of neurons in AD.

Lopes JP, Blurton-Jones M, Yamasaki TR, Agostinho P, LaFerla FM. · Center for Neuroscience and Cell Biology, Faculty of Medicine, Biochemistry Institute, University of Coimbra, Coimbra, Portugal. · J Alzheimers Dis. · Pubmed #19276549 No free full text.

Abstract: Cell cycle proteins are elevated in the brain of patients and in transgenic models of Alzheimer's disease (AD), suggesting that aberrant cell cycle re-entry plays a key role in this disorder. However, the precise relationship between cell cycle reactivation and the hallmarks of AD, amyloid-beta (Abeta) plaques and tau-laden neurofibrillary tangles, remains unclear. We sought to determine whether cell cycle reactivation initiates in direct response to Abeta and tau accumulation or whether it occurs as a downstream consequence of neuronal death pathways. Therefore, we used a triple transgenic mouse model of AD (3xTg-AD) that develops plaques and tangles, but does not exhibit extensive neuronal loss, whereas to model hippocampal neuronal death a tetracycline-regulatable transgenic model of neuronal ablation (CaM/Tet-DT(A) mice) was used. Cell-cycle protein activation was determined in these two models of neurodegeneration, using biochemical and histological approaches. Our findings indicate that Cdk4, PCNA and phospho-Rb are significantly elevated in CaM/Tet-DT(A) mice following neuronal death. In contrast, no significant activation of cell-cycle proteins occurs in 3xTg-AD mice versus non-transgenic controls. Taken together, our data indicate that neuronal cell cycle reactivation is not a prominent feature induced by Abeta or tau pathology, but rather appears to be triggered by acute neuronal loss.

Nuntagij P, Oddo S, LaFerla FM, Kotchabhakdi N, Ottersen OP, Torp R. · Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway. · J Alzheimers Dis. · Pubmed #19221421 No free full text.

Abstract: Little is known about how amyloid-beta (Abeta) is deposited in relation to the complex ultrastructure of the brain. Here we combined serial section immunoelectron microscopy with 3D reconstruction to elucidate the spatial relationship between Abeta deposits and ultrastructurally identified cellular compartments. The analysis was performed in a transgenic mouse model with mutant presenilin-1, and mutant amyloid-beta protein precursor (AbetaPP) and tau transgenes (3xTg-AD mice) and in aged dogs that develop Abeta plaques spontaneously. Reconstructions based on serial ultrathin sections of hippocampus (mice) or neocortex (dogs) that had been immunolabeled with Abeta (Abeta(1-42)) antibodies showed that the organization of extracellular Abeta deposits is more complex than anticipated from light microscopic analyses. In both species, deposits were tightly associated with plasma membranes of pyramidal cell bodies and major dendrites. The deposits typically consisted of thin sheets as well as slender tendrils that climbed along the large caliber dendritic stems of pyramidal neurons. No preferential association was observed between Abeta deposits and thin dendritic branches or spines, nor was there any evidence of preferential accumulation of Abeta around synaptic contacts or glial processes. Our data suggest that plaque formation is a precisely orchestrated process that involves specialized domains of dendrosomatic plasma membranes.

Guan H, Liu Y, Daily A, Police S, Kim MH, Oddo S, LaFerla FM, Pauly JR, Murphy MP, Hersh LB. · Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA. · J Neurosci Res. · Pubmed #19021293 No free full text.

Abstract: A number of therapeutic strategies for treating Alzheimer's disease have focused on reducing amyloid burden in the brain. Among these approaches, the expression of amyloid beta peptide (Abeta)-degrading enzymes in the brain has been shown to be effective but to date not practical for treating patients. We report here a novel strategy for lowering amyloid burden in the brain by peripherally expressing the Abeta-degrading enzyme neprilysin on leukocytes in the 3xTg-AD mouse model of Alzheimer's disease. Through transplantation of lentivirus-transduced bone marrow cells, the Abeta-degrading protease neprilysin was expressed on the surface of leukocytes. This peripheral neprilysin reduced soluble brain Abeta peptide levels by approximately 30% and lowered the accumulation of amyloid beta peptides by 50-60% when transplantation was performed at both young and early adult age. In addition, peripheral neprilysin expression reduced amyloid-dependent performance deficits as measured by the Morris water maze. Unlike other methods designed to lower Abeta levels in blood, which cause a net increase in peptide, neprilysin expression results in the catabolism of Abeta to small, innocuous peptide fragments. These findings demonstrate that peripherally expressed neprilysin, and likely other Abeta-degrading enzymes, has the potential to be utilized as a therapeutic approach to prevent and treat Alzheimer's disease and suggest that this approach should be explored further.

Oddo S, Caccamo A, Tseng B, Cheng D, Vasilevko V, Cribbs DH, LaFerla FM. · Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA. · J Neurosci. · Pubmed #19020010 links to  free full text

Abstract: The molecular alterations that induce tau pathology in Alzheimer disease (AD) are not known, particularly whether this is an amyloid-beta (Abeta)-dependent or -independent event. We addressed this issue in the 3xTg-AD mice using both genetic and immunological approaches and show that a selective decrease in Abeta(42) markedly delays the progression of tau pathology. The mechanism underlying this effect involves alterations in the levels of C terminus of heat shock protein70-interacting protein (CHIP) as we show that Abeta accumulation decreases CHIP expression and increases tau levels. We show that the Abeta-induced effects on tau were rescued by restoring CHIP levels. Our findings have profound clinical implications as they indicate that preventing Abeta accumulation will significantly alter AD progression. These data highlight the critical role CHIP plays as a link between Abeta and tau and identify CHIP as a new potential target not only for AD but for other neurodegenerative disorders characterized by tau accumulation.

Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM. · Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697-4545, USA. · J Neurosci. · Pubmed #18987186 links to  free full text

Abstract: Memory loss is the signature feature of Alzheimer's disease, and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD(+)-dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated alpha-tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of monoubiquitin-conjugated tau, suggesting that this posttranslationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau in vitro increased clearance and decreased accumulation of tau compared with wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.

Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, LaFerla FM, Callahan LM, Federoff HJ, Bowers WJ. · Department of Microbiology and Immunology, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA. · Am J Pathol. · Pubmed #18974297 links to  free full text

Abstract: Inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta, appear integral in initiating and/or propagating Alzheimer's disease (AD)-associated pathogenesis. We have previously observed a significant increase in the number of mRNA transcripts encoding the pro-inflammatory cytokine TNF-alpha, which correlated to regionally enhanced microglial activation in the brains of triple transgenic mice (3xTg-AD) before the onset of overt amyloid pathology. In this study, we reveal that neurons serve as significant sources of TNF-alpha in 3xTg-AD mice. To further define the role of neuronally derived TNF-alpha during early AD-like pathology, a recombinant adeno-associated virus vector expressing TNF-alpha was stereotactically delivered to 2-month-old 3xTg-AD mice and non-transgenic control mice to produce sustained focal cytokine expression. At 6 months of age, 3xTg-AD mice exhibited evidence of enhanced intracellular levels of amyloid-beta and hyperphosphorylated tau, as well as microglial activation. At 12 months of age, both TNF receptor II and Jun-related mRNA levels were significantly enhanced, and peripheral cell infiltration and neuronal death were observed in 3xTg-AD mice, but not in non-transgenic mice. These data indicate that a pathological interaction exists between TNF-alpha and the AD-related transgene products in the brains of 3xTg-AD mice. Results presented here suggest that chronic neuronal TNF-alpha expression promotes inflammation and, ultimately, neuronal cell death in this AD mouse model, advocating the development of TNF-alpha-specific agents to subvert AD.

Rodríguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, LaFerla FM, Oddo S, Verkhratsky A. · Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom. · PLoS One. · Pubmed #18698410 links to  free full text

Abstract: It has become generally accepted that new neurones are added and integrated mainly in two areas of the mammalian CNS, the subventricular zone and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus, which is of central importance in learning and memory. The newly generated cells display neuronal morphology, are able to generate action potentials and receive functional synaptic inputs, i.e. their properties are similar to those found in mature neurones. Alzheimer's disease (AD) is the primary and widespread cause of dementia and is an age-related, progressive and irreversible neurodegenerative disease that deteriorates cognitive functions. Here, we have used male and female triple transgenic mice (3xTg-AD) harbouring three mutant genes (beta-amyloid precursor protein, presenilin-1 and tau) and their respective non-transgenic (non-Tg) controls at 2, 3, 4, 6, 9 and 12 months of age to establish the link between AD and neurogenesis. Using immunohistochemistry we determined the area density of proliferating cells within the SGZ of the DG, measured by the presence of phosphorylated Histone H3 (HH3), and their possible co-localisation with GFAP to exclude a glial phenotype. Less than 1% of the HH3 labeled cells co-localised with GFAP. Both non-Tg and 3xTg-AD showed an age-dependent decrease in neurogenesis. However, male 3xTg-AD mice demonstrated a further reduction in the production of new neurones from 9 months of age (73% decrease) and a complete depletion at 12 months, when compared to controls. In addition, female 3xTg-AD mice showed an earlier but equivalent decrease in neurogenesis at 4 months (reduction of 63%) with an almost inexistent rate at 12 months (88% decrease) compared to controls. This reduction in neurogenesis was directly associated with the presence of beta-amyloid plaques and an increase in the number of beta-amyloid containing neurones in the hippocampus; which in the case of 3xgTg females was directly correlated. These results suggest that 3xTg-AD mice have an impaired ability to generate new neurones in the DG of the hippocampus, the severity of which increases with age and might be directly associated with the known cognitive impairment observed from 6 months of age onwards . The earlier reduction of neurogenesis in females, from 4 months, is in agreement with the higher prevalence of AD in women than in men. Thus it is conceivable to speculate that a recovery in neurogenesis rates in AD could help to rescue cognitive impairment.

Oddo S, Caccamo A, Cheng D, LaFerla FM. · Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697-4545, USA. · Brain Pathol. · Pubmed #18657136 No free full text.

Abstract: The inheritance of the epsilon4 allele of the apolipoprotein E (apoE) gene is the major genetic risk factor for developing late-onset Alzheimer disease. In transgenic mice overexpressing amyloid precursor protein (APP), replacing the endogenous mouse apoE gene with the human apolipoprotein E4 (apoE4) gene alters the distribution of amyloid-beta (Abeta) deposits from the brain parenchyma to the vasculature. However, the effects of this distribution on the onset and progression of tau pathology remain to be established. To address this issue, we used a genetic approach to replace the endogenous apoE gene with the human apoE4 allele in the 3xTg-AD mice. We showed that changing Abeta distribution from the parenchyma to the vasculature drastically reduces the tau pathology. The 3xTg-AD mice expressing the human apoE4 gene were virtually depleted of any somatodendritic tau deposits. These data strongly suggest that the somatodendritic tau accumulation is dependent on the parenchyma Abeta deposits.

Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LaFerla FM. · Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA. · J Cell Biol. · Pubmed #18591429 links to  free full text

Abstract: In addition to disrupting the regulated intramembraneous proteolysis of key substrates, mutations in the presenilins also alter calcium homeostasis, but the mechanism linking presenilins and calcium regulation is unresolved. At rest, cytosolic Ca(2+) is maintained at low levels by pumping Ca(2+) into stores in the endoplasmic reticulum (ER) via the sarco ER Ca(2+)-ATPase (SERCA) pumps. We show that SERCA activity is diminished in fibroblasts lacking both PS1 and PS2 genes, despite elevated SERCA2b steady-state levels, and we show that presenilins and SERCA physically interact. Enhancing presenilin levels in Xenopus laevis oocytes accelerates clearance of cytosolic Ca(2+), whereas higher levels of SERCA2b phenocopy PS1 overexpression, accelerating Ca(2+) clearance and exaggerating inositol 1,4,5-trisphosphate-mediated Ca(2+) liberation. The critical role that SERCA2b plays in the pathogenesis of Alzheimer's disease is underscored by our findings that modulating SERCA activity alters amyloid beta production. Our results point to a physiological role for the presenilins in Ca(2+) signaling via regulation of the SERCA pump.

Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F, Tsukagoshi-Nagai H, Horikoshi-Sakuraba Y, Mughal M, Rebeck GW, LaFerla FM, Mattson MP, Iwata N, Saido TC, Klein WL, Duff KE, Aisen PS, Matsuoka Y. · Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. · Brain Res. · Pubmed #18486110 No free full text.

Abstract: Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta (Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology. We also found an increase in beta-secretase activity and a reduction of neprilysin in female mice compared to males; this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females. In contrast to significantly more aggressive Abeta pathology in females, gender did not affect the levels of phosphorylated tau in 3xTg-AD mice. These results point to the involvement of Abeta pathways in the higher risk of AD in women. In addition to comparison of pathology between genders at 9, 16 and 23 months of age, we examined the progression of Abeta pathology at additional age points; i.e., brain Abeta load, intraneuronal oligomeric Abeta distribution and plaque load, in male 3xTg-AD mice at 3, 6, 9, 12, 16, 20 and 23 months of age. These findings confirm progressive Abeta pathology in 3xTg-AD transgenic mice, and provide guidance for their use in therapeutic research.

McKee AC, Carreras I, Hossain L, Ryu H, Klein WL, Oddo S, LaFerla FM, Jenkins BG, Kowall NW, Dedeoglu A. · Department of Neurology, Boston University School of Medicine, Boston, MA, USA. · Brain Res. · Pubmed #18374906 links to  free full text

Abstract: We examined the effects of ibuprofen on cognitive deficits, Abeta and tau accumulation in young triple transgenic (3xTg-AD) mice. 3xTg-AD mice were fed ibuprofen-supplemented chow between 1 and 6 months. Untreated 3xTg-AD mice showed significant impairment in the ability to learn the Morris water maze (MWM) task compared to age-matched wild-type (WT) mice. The performance of 3xTg-AD mice was significantly improved with ibuprofen treatment compared to untreated 3xTg-AD mice. Ibuprofen-treated transgenic mice showed a significant decrease in intraneuronal oligomeric Abeta and hyperphosphorylated tau (AT8) immunoreactivity in the hippocampus. Confocal microscopy demonstrated co-localization of conformationally altered (MC1) and early phosphorylated tau (CP-13) with oligomeric Abeta, and less co-localization of oligomeric Abeta and later forms of phosphorylated tau (AT8 and PHF-1) in untreated 3xTg-AD mice. Our findings show that prophylactic treatment of young 3xTg-AD mice with ibuprofen reduces intraneuronal oligomeric Abeta, reduces cognitive deficits, and prevents hyperphosphorylated tau immunoreactivity. These findings provide further support for intraneuronal Abeta as a cause of cognitive impairment, and suggest that pathological alterations of tau are associated with intraneuronal oligomeric Abeta accumulation.

Carroll JC, Rosario ER, Chang L, Stanczyk FZ, Oddo S, LaFerla FM, Pike CJ. · Neuroscience Graduate Program, Davis School of Gerontology, University of Southern California, Los Angeles, California 90089, USA. · J Neurosci. · Pubmed #18045930 links to  free full text

Abstract: Estrogen depletion in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD), and estrogen-based hormone therapy may reduce this risk. However, the effects of progesterone both alone and in combination with estrogen on AD neuropathology remain unknown. In this study, we used the triple transgenic mouse model of AD (3xTg-AD) to investigate the individual and combined effects of estrogen and progesterone on beta-amyloid (Abeta) accumulation, tau hyperphosphorylation, and hippocampal-dependent behavioral impairments. In gonadally intact female 3xTg-AD mice, AD-like neuropathology was apparent by 3 months of age and progressively increased through age 12 months, a time course that was paralleled by behavioral impairment. Ovariectomy-induced depletion of sex steroid hormones in adult female 3xTg-AD mice significantly increased Abeta accumulation and worsened memory performance. Treatment of ovariectomized 3xTg-AD mice with estrogen, but not progesterone, prevented these effects. When estrogen and progesterone were administered in combination, progesterone blocked the beneficial effect of estrogen on Abeta accumulation but not on behavioral performance. Interestingly, progesterone significantly reduced tau hyperphosphorylation when administered both alone and in combination with estrogen. These results demonstrate that estrogen and progesterone independently and interactively regulate AD-like neuropathology and suggest that an optimized hormone therapy may be useful in reducing the risk of AD in postmenopausal women.

Yamasaki TR, Blurton-Jones M, Morrissette DA, Kitazawa M, Oddo S, LaFerla FM. · Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA. · J Neurosci. · Pubmed #17978032 links to  free full text

Abstract: Neuronal loss is a major pathological outcome of many common neurological disorders, including ischemia, traumatic brain injury, and Alzheimer disease. Stem cell-based approaches have received considerable attention as a potential means of treatment, although it remains to be determined whether stem cells can ameliorate memory dysfunction, a devastating component of these disorders. We generated a transgenic mouse model in which the tetracycline-off system is used to regulate expression of diphtheria toxin A chain. After induction, we find progressive neuronal loss primarily within the hippocampus, leading to specific impairments in memory. We find that neural stem cells transplanted into the brain after neuronal ablation survive, migrate, differentiate and, most significantly, improve memory. These results show that stem cells may have therapeutic value in diseases and conditions that result in memory loss.