Alzheimer Disease: Federoff HJ

Tyler CM, Federoff HJ. · Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester NY 14642, USA. · Cell Transplant. · Pubmed #16719061 No free full text.

Abstract: Gene therapy is a potentially promising new treatment for neurodegenerative disorders such as Alzheimer's disease (AD), which has been difficult to treat with conventional therapeutics. Viral vector-mediated somatic gene therapy is a rapidly developing methodology for providing never before achieved capability to deliver specific genes to the CNS in a highly localized and controlled manner. With the advent and refinements of this technology one focus is directed to which genes are the most appropriate to select for specific disease indications. Nerve growth factor (NGF), a potent survival factor for critical cell populations that degenerate in AD, has been chosen already for clinical gene therapy trials in human AD patients. Much knowledge about the pathophysiological underpinnings of AD is still lacking to make clear which patients may benefit from a gene therapy approach. Moreover, a detailed understanding of sustained NGF action in the normal and diseased CNS needs to be resolved before conclusions can be drawn regarding the utility of NGF gene therapy. Systematic efforts to acquire this new knowledge should compel clinically and biologically sophisticated efforts to advance gene therapy for neurodegenerative diseases.

Federoff HJ, Bowers WJ. · Department of Neurology, Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. · Sci Aging Knowledge Environ. · Pubmed #16293586 links to  free full text

Abstract: Given the emotional, social, and financial devastation wrought by Alzheimer's disease (AD), it is imperative that effective therapeutics be devised to ameliorate this presently incurable disorder. Vaccine-based approaches have been developed to target and eliminate amyloid beta (Abeta), a key peptide implicated in AD pathogenesis. Preclinical successes in AD mouse models created excitement and impetus for the clinical application of an Abeta-based vaccine. Eliciting immune responses against a self-peptide (that is, a peptide produced by the organism itself), such as Abeta, carries with it the potential to induce autoimmune and inflammatory conditions in the vaccinated individual, a caveat borne out in multiple patients enrolled as part of a recent clinical trial. These clinical adverse events seemingly overshadowed interesting behavioral stabilization and alterations of Abeta burden in these and other vaccinated patients, thus speaking to the potential of immunotherapy for AD. Understanding the mechanisms by which vaccines reduce Abeta burden in AD brain and the types of immune responses raised, as well as developing new modalities of vaccine delivery that facilitate the modulation of elicited immune responses, will undoubtedly lead to a new generation of efficacious Abeta immunotherapeutics with improved safety profiles.

Tariot PN, Federoff HJ. · Department of Psychiatry, University of Rochester Medical Center, Rochester, New York, USA. · Alzheimer Dis Assoc Disord. · Pubmed #14512816 No free full text.

Abstract: A cascade of pathophysiological events is triggered in Alzheimer disease (AD) that ultimately involves common cellular signaling pathways and leads to cellular and network dysfunction, failure of neurotransmission, cell death, and a common clinical outcome. The process is asynchronous, meaning that viable neurons remain as targets for therapy even in the diseased state, and each stage of the cascade affords the possibility for therapeutic intervention. Cholinesterase inhibitors are the only available treatment in the United States for patients with mild to moderate AD, helping maintain cognitive and functional abilities in most patients and conferring beneficial behavioral effects in some. Memantine is an NMDA receptor antagonist that has recently been approved in Europe for treatment of moderately severe to severe AD and is under investigation in the United States. Its mechanism of action may include enhanced neurotransmission in several systems as well as antiexcitotoxic effects. There are data regarding the effectiveness of the combination of memantine with cholinesterase inhibitors that will be useful for the practicing clinician. Other agents have shown some benefit in clinical trials, including the antioxidants vitamin E, selegiline, and Ginkgo biloba extracts, although the weight of evidence regarding their effects is not sufficient to define clinical practice. Potential future therapies currently are in development that target multiple aspects of the illness cascade, including aberrant inflammation, neurotrophic function, and processing of beta amyloid and tau proteins. These newer approaches hold promise for disease modification but are as yet unproven. Whether or not disease-modifying or preventive therapies become a reality, clinicians will be faced with AD patients who require treatment at all stages of illness for the indefinite future. Cholinergic and emerging noncholinergic medications will likely prevail as the standards of treatment for years to come.

Bowers WJ, Federoff HJ. · Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA. · Neurobiol Aging. · Pubmed #12392770 No free full text.

This publication has no abstract.

Maguire-Zeiss KA, Bowers WJ, Federoff HJ. · Department of Neurology, University of Rochester School of Medicine and Dentistry, NY 14642, USA. · Curr Opin Mol Ther. · Pubmed #11699893 No free full text.

Abstract: The efficient and targeted transfer of genes is the goal of gene therapy. In the central nervous system (CNS), this is challenging due in part to the exquisite anatomy of the brain. Herpes simplex virus (HSV) vectors are particularly amenable to CNS therapies as they are capable of transducing a variety of cells, have a large transgene capacity and can exist as either oncolytic or non-immunogenic vectors. The versatility of this vector platform and its potential molecular therapeutic use in two CNS disorders, Alzheimer's disease and malignant brain tumors, will be discussed.

Federoff HJ. · University of Rochester Medical Center, Center for Aging and Developmental Biology, NY 14642, USA. · Neurobiol Aging. · Pubmed #10604442 No free full text.

This publication has no abstract.

Mhyre TR, Loy R, Tariot PN, Profenno LA, Maguire-Zeiss KA, Zhang D, Coleman PD, Federoff HJ. · Center for Aging and Developmental Biology, Aab Institute for Biomedical Research, University of Rochester School of Medicine and Dentistry, Box 645, 601 Elmwood Avenue, Rochester, NY 14642, USA. · Neurobiol Aging. · Pubmed #17521776 No free full text.

Abstract: The molecular profiling of peripheral tissues, including circulating leukocytes, may hold promise in the discovery of biomarkers for diagnosing and treating neurodegenerative diseases, including Alzheimer's disease (AD). As a proof-of-concept, we performed a proteomics study on peripheral leukocytes from patients with AD both before and during treatment with divalproex sodium. Using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, we identified 10 differentially expressed proteins: two up-regulated proteins, 14-3-3 protein epsilon and peroxiredoxin 2; and eight down-regulated proteins, actin-interacting protein, mitogen activated protein kinase 1, beta actin, annexin A1, glyceraldehyde 3-phosphate dehydrogenase, transforming protein RhoA, acidic leucine-rich nuclear phosphoprotein 32 family member B, and a currently unidentified protein. A subset was validated on both the transcript and protein levels in normal human peripheral blood mononuclear cell cultures treated with valproic acid. These proteins comprise a number of functional classes that may be important to the biology of AD and to the therapeutic action of valproate. These data also suggest the potential of using peripheral leukocytes to monitor pharmaceutical action for neurodegenerative diseases.

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.

Frazer ME, Hughes JE, Mastrangelo MA, Tibbens JL, Federoff HJ, Bowers WJ. · Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. · Mol Ther. · Pubmed #18388924 links to  free full text

Abstract: Immunotherapeutics designed to dissolve existing amyloid plaques or to interrupt amyloid-beta (Abeta) accumulation may be feasible for treatment and/or prevention of Alzheimer's disease (AD). "Shaping" the immune responses elicited against Abeta is requisite toward generating an efficacious and safe outcome; this can be achieved by minimizing the possibility of deleterious inflammatory reactions in the brain as observed in clinical testing of Abeta peptide/adjuvant-based modalities. Herpes simplex virus (HSV)-based amplicons can coexpress multiple antigens and/or immunomodulatory genes due to their large genetic size capacity, thereby facilitating antigen-specific immune response shaping. We have constructed an amplicon (HSV(IE)Abeta(CMV)IL-4) that co-delivers Abeta(1-42) with interleukin-4 (IL-4), a cytokine that promotes the generation of Th2-like T-cell responses, which are favored in the setting of AD immunotherapy. Triple-transgenic AD (3xTg-AD) mice, which progressively develop both amyloid and neurofibrillary tangle pathology, were vaccinated thrice with HSV(IE)Abeta(CMV)IL-4, or a set of control amplicon vectors. Increased Th2-related, Abeta-specific antibodies, improved learning and functioning of memory, and prevention of AD-related amyloid and tau pathological progression were observed significantly more in the HSV(IE)Abeta(CMV)IL-4 vaccinated mice as compared to the other experimental groups. Our study underscores the potential of Abeta immunotherapy for AD and highlights the potency of amplicons in facilitating the immune response modulation to a disease-relevant antigen.

Henricksen LA, Federoff HJ. · Center for Aging and Developmental Biology, Aab Institute for Biomedical Sciences, University of Rochester School of Medicine and Dentistry, Rochester, MN, USA. · J Alzheimers Dis. · Pubmed #15665413 No free full text.

Abstract: Herein a case is made for the development of novel cytoprotective approaches based upon molecular mechanisms thought to underlie the caloric restriction phenomenon. This analysis leads to the prediction that molecular genetic perturbations affecting the metabolism of nuclear NAD(+) and metabolites will be neuroprotective.

Bowers WJ, Mastrangelo MA, Stanley HA, Casey AE, Milo LJ, Federoff HJ. · Department of Neurology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA. · Neurobiol Aging. · Pubmed #15653168 links to  free full text

Abstract: Given the participation of amyloid beta (Abeta) in Alzheimer's disease (AD) pathogenesis the derivation of experimental therapeutics to prevent Abeta fibrillogenesis and/or enhance removal of parenchymal amyloid deposits represent viable disease-modifying approaches. Active Abeta-based immunotherapies have shown promise in mouse AD models, but application in human trials was accompanied by moderate brain inflammation in a subset of patients. Immune-shaping vaccine platforms may mitigate adverse effects. Herein, we describe the use of herpes simplex virus (HSV)-derived amplicons to elicit distinctive immune responses against Abeta. Two vaccine vectors were constructed: one expressing Abeta1-42 alone (HSVAbeta), and a second expressing Abeta1-42 fused with the molecular adjuvant tetanus toxin Fragment C (HSVAbeta/TtxFC). Peripheral administration of these vaccines augmented humoral responses to Abeta and reduced CNS Abeta deposition in Tg2576 AD mice. Interestingly and unexpectedly, HSVAbeta vaccination was uniquely toxic and incited the expression of pro-inflammatory molecule transcripts within the hippocampi of Tg2576 mice, suggesting that this paradigm may serve as a relevant model to study Abeta vaccine-elicited CNS inflammatory syndromes.

Federoff HJ. · No affiliation provided · Gene Ther. · Pubmed #19202630 No free full text.

This publication has no abstract.