Alzheimer Disease: Jacobsen JS

Ryan JM, Schneider G, Jacobsen JS. · Neuroscience Global Clinical Research and Development, Wyeth Research, Collegeville, PA, USA. · Alzheimers Dement. · Pubmed #19328445 No free full text.

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Jacobsen JS, Reinhart P, Pangalos MN. · Wyeth Research, Neuroscience Discovery, CN8000, Princeton, New Jersey 08543, USA. · NeuroRx. · Pubmed #16489369 links to  free full text

Abstract: Alzheimer's disease is a progressive neurodegenerative disorder and the leading cause of dementia in the Western world. Postmortem, it is characterized neuropathologically by the presence of amyloid plaques, neurofibrillary tangles, and a profound gray matter loss. Neurofibrillary tangles are composed of an abnormally hyperphosphorylated intracellular protein called tau, tightly wound into paired helical filaments and thought to impact microtubule assembly and protein trafficking, resulting in the eventual demise of neuronal viability. The extracellular amyloid plaque deposits are composed of a proteinacious core of insoluble aggregated amyloid-beta (Abeta) peptide and have led to the foundation of the amyloid hypothesis. This hypothesis postulates that Abeta is one of the principal causative factors of neuronal death in the brains of Alzheimer's patients. With multiple drugs now moving through clinical development for the treatment of Alzheimer's disease, we will review current and future treatment strategies aimed at improving both the cognitive deficits associated with the disease, as well as more novel approaches that may potentially slow or halt the deadly neurodegenerative progression of the disease.

Jacobsen JS. · Neuroscience Discovery Research, Wyeth Research, CN-8000, Princeton, New Jersey, 08543-8000, USA. · Curr Top Med Chem. · Pubmed #11966458 No free full text.

Abstract: Alzheimer's Disease (AD) is a progressive neurodegenerative disease that is prevalent among the elderly. It is a heterogeneous disease involving a number of genetic components, risk factors and other poorly defined elements that all impact on the accumulation of beta-amyloid peptide (Abeta). Current understanding of pathology, biochemistry and genetics strengthens the notion that Abeta is potentially the common pathogenic agent in an apparent convergence of various mechanisms leading to the decline of cognitive function and neuronal loss. While many issues remain controversial, recent evidence attributing Abeta accumulation to cognitive decline in humans, coupled to the demonstrated improvement of cognitive function following Abeta immunization in pre-clinical models, strongly supports the "amyloid hypothesis" and a central role for Abeta; in the pathophysiology and etiology of AD. These and other observations endorse the notion that therapeutic strategies targeting the inhibition of Abeta accumulation by the use of protease inhibitors,immunization or other strategies, may provide disease-altering interventions to the development and progression of AD. The only approved and marketed treatments currently available for AD are the acetylcholinesterase inhibitors, a palliative strategy aimed at the temporary improvement of cognitive function. The purpose of this overview is to provide a brief understanding of key events leading to the progression of AD and to highlight a few of the current and most promising therapeutic strategies that one day might be available for the treatment of AD.

Mayer SC, Kreft AF, Harrison B, Abou-Gharbia M, Antane M, Aschmies S, Atchison K, Chlenov M, Cole DC, Comery T, Diamantidis G, Ellingboe J, Fan K, Galante R, Gonzales C, Ho DM, Hoke ME, Hu Y, Huryn D, Jain U, Jin M, Kremer K, Kubrak D, Lin M, Lu P, Magolda R, Martone R, Moore W, Oganesian A, Pangalos MN, Porte A, Reinhart P, Resnick L, Riddell DR, Sonnenberg-Reines J, Stock JR, Sun SC, Wagner E, Wang T, Woller K, Xu Z, Zaleska MM, Zeldis J, Zhang M, Zhou H, Jacobsen JS. · Chemical and Screening Sciences, and Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. · J Med Chem. · Pubmed #19012391 No free full text.

Abstract: SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.

Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, Warwick HK, Ring RH, Kirksey Y, Aschmies S, Xu J, Kubek K, Hirst WD, Gonzales C, Chen Y, Murphy E, Leonard S, Vasylyev D, Oganesian A, Martone RL, Pangalos MN, Reinhart PH, Jacobsen JS. · Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543, USA. · Mol Cell Neurosci. · Pubmed #17336088 No free full text.

Abstract: Recent studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein to Abeta peptide. Moreover, cholesterol-rich apoE-containing lipoproteins may also promote Abeta clearance. Agonists of the liver X receptor (LXR) transcriptionally induce genes involved in intracellular lipid efflux and transport, including apoE. Thus, LXR agonists have the potential to both inhibit APP processing and promote Abeta clearance. Here we show that LXR agonist, TO901317, increased hippocampal ABCA1 and apoE and decreased Abeta42 levels in APP transgenic mice. TO901317 had no significant effects on levels of Abeta40, full length APP, or the APP processing products. Next, we examined the effects of TO901317 in the contextual fear conditioning paradigm; TO901317 completely reversed the contextual memory deficit in these mice. These data demonstrate that LXR agonists do not directly inhibit APP processing but rather facilitate the clearance of Abeta42 and may represent a novel therapeutic approach to Alzheimer's disease.

Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE. · Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA. · Proc Natl Acad Sci U S A. · Pubmed #16549764 links to  free full text

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of beta-amyloid (Abeta)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the Abeta42/Abeta40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until approximately 18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.

Comery TA, Martone RL, Aschmies S, Atchison KP, Diamantidis G, Gong X, Zhou H, Kreft AF, Pangalos MN, Sonnenberg-Reines J, Jacobsen JS, Marquis KL. · Discovery Neuroscience, Wyeth Research, CN8000, Princeton, New Jersey 08543, USA. · J Neurosci. · Pubmed #16192379 links to  free full text

Abstract: Transgenic mice (Tg2576) overexpressing the Swedish mutation of the human amyloid precursor protein display biochemical, pathological, and behavioral markers consistent with many aspects of Alzheimer's disease, including impaired hippocampal function. Impaired, hippocampal-dependent, contextual fear conditioning (CFC) is observed in mice as young as 20 weeks of age. This impairment can be attenuated after treatment before training with the phosphodiesterase-4 inhibitor rolipram (0.1 mg/kg, i.p.). A rolipram-associated improvement is also observed in the littermate controls, suggesting that the effect of rolipram is independent of beta-amyloid. Acute treatment before training (but not after training or before testing) with the gamma-secretase inhibitor (GSI) N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine-t-butylester (DAPT), at a dose that reduces brain concentrations of beta-amyloid (100 mg/kg), attenuates the impairment in 20- to 65-week-old Tg2576 mice. Importantly, DAPT had no effect on performance of control littermates. These data are supportive of a role of beta-amyloid in the impairment of CFC in Tg2576 mice. Furthermore, they suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.

Kajkowski EM, Lo CF, Ning X, Walker S, Sofia HJ, Wang W, Edris W, Chanda P, Wagner E, Vile S, Ryan K, McHendry-Rinde B, Smith SC, Wood A, Rhodes KJ, Kennedy JD, Bard J, Jacobsen JS, Ozenberger BA. · Wyeth Neuroscience, Wyeth-Ayerst Research, CN 8000, Princeton, New Jersey 08543-8000, USA. · J Biol Chem. · Pubmed #11278849 links to  free full text

Abstract: Degeneration of neurons in Alzheimer's disease is mediated by beta-amyloid peptide by diverse mechanisms, which include a putative apoptotic component stimulated by unidentified signaling events. This report describes a novel beta-amyloid peptide-binding protein (denoted BBP) containing a G protein-coupling module. BBP is one member of a family of three proteins containing this conserved structure. The BBP subtype bound human beta-amyloid peptide in vitro with high affinity and specificity. Expression of BBP in cell culture induced caspase-dependent vulnerability to beta-amyloid peptide toxicity. Expression of a signaling-deficient dominant negative BBP mutant suppressed sensitivity of human Ntera-2 neurons to beta-amyloid peptide mediated toxicity. These findings suggest that BBP is a target of neurotoxic beta-amyloid peptide and provide new insight into the molecular pathophysiology of Alzheimer's disease.

Johnsingh AA, Johnston JM, Merz G, Xu J, Kotula L, Jacobsen JS, Tezapsidis N. · Department of Psychiatry, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1229, New York, NY 10029, USA. · FEBS Lett. · Pubmed #10620705 No free full text.

Abstract: The majority of familial Alzheimer's disease (AD) cases are linked to mutations on presenilin 1 and 2 genes (PS1 and PS2). The normal function of the proteins and the mechanisms underlying early-onset AD are currently unknown. To address this, we screened an expression library for proteins that bind differentially to the wild-type PS1 and mutant in the large cytoplasmic loop (PS1L). Thus we isolated the C-terminal tail of the 170 kDa cytoplasmic linker protein (CLIP-170) and Reed-Sternberg cells of Hodgkin's disease-expressed intermediate filament-associated protein (Restin), cytoplasmic proteins linking vesicles to the cytoskeleton. PS1L binding to CLIP-170/restin requires Ca(2+). Treating cells with thapsigargin or ionomycin increased the mutated PS1 in CLIP-170 immunoprecipitates. Further, PS1 and CLIP-170 co-localize in transfected cells and neuronal cultures.