Alzheimer Disease: Banks WA

Banks WA, Morley JE. · No affiliation provided · J Gerontol A Biol Sci Med Sci. · Pubmed #12663694 No free full text.

This publication has no abstract.

Banks WA. · GRECC, Veterans Affairs Medical Center-St. Louis, and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, 915 N. Grand Blvd, St. Louis, MO 63106, USA. · BMC Neurosci. · Pubmed #19090999 links to  free full text

Abstract: Development of therapeutics for the central nervous system is one of the most challenging areas in drug development. This is primarily because, in addition to all of the other complications one faces in developing new drugs targeting peripheral sites, one must also negotiate the blood-brain barrier (BBB). There are dozens of strategies to overcome the obstacle of the BBB, but many of these are bound to fail, barring extreme serendipity, because they are based on an inaccurate or incomplete picture of the BBB. This article therefore starts with a brief review of the BBB as it pertains to drug development. It then examines some examples of the delivery of drugs to the central nervous system that are relevant to Alzheimer's disease, placing emphasis on peptides, antibodies, and antisense oligonucleotides.

Jaeger LB, Banks WA. · Department of Pharmacological and Physiological Science, St. Louis University, MO, USA. · Methods Mol Med. · Pubmed #15375320 No free full text.

This publication has no abstract.

Jaeger LB, Banks WA. · Saint Louis University School of Medicine, Department of Pharmacology and Physiology, USA. · Front Biosci. · Pubmed #14977581 No free full text.

Abstract: Antisense oligonucleotides (ONs) have great therapeutic potential for conditions in which aberrant protein production results in pathology. This method of reducing the expression of a target gene is both precise and sequence-specific. Although there are many applications for antisense ONs as central nervous system (CNS) therapeutics, systemically administered antisense ONs must be capable of crossing the blood-brain barrier (BBB) in quantities effective enough to alter protein production in the CNS. Because antisense ONs are large, highly polar molecules, their rate of transport across the BBB is likely to be low. Recent studies have shown that antisense ONs are capable of crossing the BBB without the aid of a carrier system, however little is known about the molecular mechanisms which mediate this transport. This review will focus on nucleic acid chemistries suitable for in vivo research and their potential applications in the treatment of CNS disease.

Kumar VB, Franko M, Banks WA, Kasinadhuni P, Farr SA, Vyas K, Choudhuri V, Morley JE. · Division of Geriatric Research, Education and Clinical Center, VA Medical Center, St Louis, MO 63125, USA. · J Exp Biol. · Pubmed #19181896 links to  free full text

Abstract: Senescence-accelerated mice (SAMP8) serve as a model for Alzheimer's disease (AD) as they exhibit early loss of memory and increased amyloid precursor protein (APP) expression. APP is a ubiquitous membrane protein that is physiologically processed by site-specific proteolysis firstly by alpha- or beta-secretases, releasing a large fragment called APP(S) that contains most of the extracellular sequences of APP, a small extracellular stub, the transmembrane region and the cytoplasmic tail of APP (;AICD'-APP intracellular domain). These are subsequently cleaved by gamma-secretase at multiple sites in the transmembrane region, releasing small peptides, Abeta(1-40) and Abeta(1-42), the major components of AD-associated amyloid fibrils. gamma-secretase is a high-molecular-mass complex composed of presenilin-1 (PS1), nicastrin, APH-1 and Pen-2. As PS1 has been shown to play a critical role in facilitating gamma-secretase activity, and mutations in this protein are associated with familial AD (FAD), we have cloned it from SAMP8 mouse hippocampus and compared its sequence with those of other species. Furthermore, changes in the expression of PS1 with age in the hippocampal tissue of SAMP8 were studied. The results showed that the SAMP8 PS1 cDNA sequence is identical to that of normal mice. However, its expression in the hippocampus of SAMP8 exhibited an increase, while CD-1 mice, a strain that does not exhibit premature memory loss, showed no change with age. An increased amount or mutation(s) in PS1, which alters the stoichiometric balance of the gamma-secretase complex, may be the cause of aberrant or increased processing of APP, resulting in Abeta accumulation leading to loss of memory.

Dogrukol-Ak D, Kumar VB, Ryerse JS, Farr SA, Verma S, Nonaka N, Nakamachi T, Ohtaki H, Niehoff ML, Edwards JC, Shioda S, Morley JE, Banks WA. · Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey. · J Cereb Blood Flow Metab. · Pubmed #19002200 No free full text.

Abstract: By isolating for the first time ever a peptide transporter from the blood-brain barrier (BBB) and developing an antisense that selectively targets the brain-to-blood efflux component, we were able to deliver a therapeutic concentration of the neurotrophic peptide pituitary adenylate cyclase-activating polypeptide (PACAP) 27 to brain in animal models of Alzheimer's and stroke. Efflux pumps at the BBB are major causes of BBB impermeability to peptides. PACAP is neuroprotective in vitro in femtomole amounts, but brain uptake of PACAP27 is limited by an efflux component of peptide transport system-6 (PTS-6). Here, we characterized, isolated, and sequenced this component of PTS-6, identifying it as beta-F1 ATPase, and colocalized it with PACAP27 on BBB endothelial cells. Antisenses targeting the BBB inhibited PACAP27 efflux, thus increasing brain uptake of PACAP27. Treatment with antisense+PACAP27 improved cognition in a mouse model of Alzheimer's disease and reduced infarct size after cerebral ischemia. This represents the first isolation from BBB tissue of a peptide transporter and shows that inhibition of peptide efflux pumps is a potential strategy for drug delivery to brain.

Banks WA, Farr SA, Morley JE, Wolf KM, Geylis V, Steinitz M. · Geriatrics Research Educational and Clinical Center, Veterans Affairs Medical Center-St. Louis, MO 63106, USA. · Exp Neurol. · Pubmed #17582399 links to  free full text

Abstract: Amyloid beta protein (Abeta) levels are elevated in the brain of Alzheimer's disease patients. Anti-Abeta antibodies can reverse the histologic and cognitive impairments in mice which overexpress Abeta. Passive immunization appears safer than vaccination and treatment of patients will likely require human rather than xenogenic antibodies. Effective treatment will likely require antibody to cross the blood-brain barrier (BBB). Unfortunately, antibodies typically cross the BBB very poorly and accumulate less well in brain than even albumin, a substance nearly totally excluded from the brain. We compared the ability of two anti-Abeta human monoclonal IgM antibodies, L11.3 and HyL5, to cross the BBB of young CD-1 mice to that of young and aged SAMP8 mice. The SAMP8 mouse has a spontaneous mutation that induces an age-related, Abeta-dependent cognitive deficit. There was preferential uptake of intravenously administered L11.3 in comparison to HyL5, albumin, and a control human monoclonal IgM (RF), especially by hippocampus and olfactory bulb in aged SAMP8 mice. Injection of L11.3 into the brains of aged SAMP8 mice reversed both learning and memory impairments in aged SAMP8 mice, whereas IgG and IgM controls were ineffective. Pharmacokinetic analysis predicted that an intravenous dose 1000 times higher than the brain injection dose would reverse cognitive impairments. This predicted intravenous dose reversed the impairment in learning, but not memory, in aged SAMP8 mice. In conclusion, an IgM antibody was produced that crosses the BBB to reverse cognitive impairment in a murine model of Alzheimer's disease.

Farr SA, Banks WA, Uezu K, Gaskin FS, Morley JE. · Geriatric Research Education and Clinical Center (GRECC), VA Medical Center, St. Louis, MO, USA. · Life Sci. · Pubmed #15464829 No free full text.

Abstract: Dehydroepiandrosterone sulfate (DHEAS) has been reported to improve memory in aged animals and suggested as a treatment for age-related dementias. The SAMP8 mouse, a model of Alzheimer's disease, has an age-related impairment in learning and memory and an increase in brain levels of amyloid precursor protein (APP) and amyloid beta protein (Abeta). Male SAMP8 mice also have a decrease in testosterone, to which DHEA is a precursor. Diabetes has been suggested as a model of aging and to be linked to Alzheimer's disease. Diabetics can have memory deficits and lower DHEAS levels. Here, we examined the effects of chronic oral DHEAS on acquisition and retention for T-maze footshock avoidance in 12 mo male SAMP8 mice and in CD-1 mice with streptozocin-induced diabetes. Learning and memory were improved in aged SAMP8 mice, but not in CD-1 mice with streptozocin-induced diabetes. These findings suggest that DHEAS is more effective in reversing the cognitive impairments associated with overexpression of Abeta than with diabetes.

Poon HF, Joshi G, Sultana R, Farr SA, Banks WA, Morley JE, Calabrese V, Butterfield DA. · Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington 40506-0055, USA. · Brain Res. · Pubmed #15262209 No free full text.

Abstract: Amyloid beta-peptide (Abeta) is known to induce free radical-mediated oxidative stress in the brain. Free radical-mediated damage to the neuronal membrane components has been implicated in the etiology of Alzheimer's disease (AD). Abeta is produced by proteolytic processing of the amyloid precursor protein (APP). The senescence accelerated mouse prone 8 (SAMP8) strain was developed by phenotypic selection from a common genetic pool. The SAMP8 strain exhibits age-related deterioration in memory and learning as well as Abeta accumulation, and it is considered an effective model for studying brain aging in accelerated senescence. Previous research has shown that a phosphorothiolated antisense oligonucleotide directed against the Abeta region of APP decreases the expression of APP and reverses deficits in learning and memory in aged SAMP8 mice. Consistent with other reports, our previous study showed that 12-month-old SAMP8 mice have increased levels of oxidative stress markers in the brain compared with that in brains from 4-month-old SAMP8 mice. In the current study, 12-month-old SAMP8 mice were treated with antisense oligonucleotide directed against the Abeta region of APP, and the oxidative markers in brain were decreased significantly. Therefore, we conclude that Abeta may contribute to the oxidative stress found in aged SAMP8 mice that have learning and memory impairments. These results are discussed in reference to AD.

Banks WA, Farr SA. · Department of Internal Medicine, Saint Louis University School of Medicine, MO 63104, USA. · Clin Geriatr Med. · Pubmed #15182884 No free full text.

Abstract: The interaction of bedside and basic science has led to the identification ofa short list of pathological proteins as causal in Alzheimer's disease. AI3P has received the most attention, and work with animal models has reinforced the evidence that overproduction of ABP causes cognitive impairments. Animal models are now being used to discover and develop unique therapeutics directed at reversing the deleterious effects of ABP. These models strongly suggest that established Alzheimer's disease might be reversible, not just preventable. Animal models are also demonstrating that other peptides and proteins can enhance or impair cognitive function. These peptides and proteins add further to the list of possible therapeutic candidates. Approaches such as these, and not the commercial antiaging remedies that have no scientific basis, will eventually provide medicine for memory enhancement.

Banks WA, Robinson SM, Verma S, Morley JE. · Geriatrics Research Educational and Clinical Center, Veterans Affairs Medical Center-St. Louis and Division of Geriatrics, Department of Internal Medicine, St. Louis University School of Medicine, St. Louis, MO 63106, USA. · Neuroscience. · Pubmed #14522007 No free full text.

Abstract: Brain to blood transport is believed to be a major determinant of the amount of amyloid beta protein (AbetaP) found in brain. Impaired efflux has been suggested as a mechanism by which AbetaP can accumulate in the CNS and so lead to Alzheimer's disease (AD). To date, however, no study of the efflux of the form of AbetaP most relevant to AD, AbetaP1-42, has been conducted, even though a single amino acid substitution in AbetaP can greatly alter efflux. Here, we examined the efflux of AbetaP mouse1-42, mouse1-40, human1-42, and human1-40 in young CD-1, young senesence accelerated mouse (SAM) P8, and aged SAMP8 mice. The SAMP8 mouse with aging spontaneously overproduces AbetaP and develops cognitive impairments reversed by AbetaP-directed antibody or phosphorothioate antisense oligonucleotide. CD-1 mice transported all forms of AbetaP, although mouse1-42 and human1-40 were transported faster than the other forms. There was a decrease in the saturable transport of mouse1-42 in SAMP8 mice regardless of age. Efflux of mouse1-40 and human1-42 was only by a non-saturable mechanism in young SAMP8 mice and their efflux was totally absent in aged SAMP8 mice. These differences in the efflux of the various forms of AbetaP among the three groups of mice supports the hypothesis that impaired efflux is an important factor in the accumulation of AbetaP in the CNS.

Adessi C, Frossard MJ, Boissard C, Fraga S, Bieler S, Ruckle T, Vilbois F, Robinson SM, Mutter M, Banks WA, Soto C. · Serono Pharmaceutical Research Institute, 1228 Geneva, Switzerland. · J Biol Chem. · Pubmed #12578830 links to  free full text

Abstract: Amyloid plaques in brain, composed of aggregates of amyloid-beta peptide, play a central role in the pathogenesis of Alzheimer's disease and represent a good target for treatment. We have shown previously that a 5-amino acid beta-sheet breaker peptide (iA beta 5p), end-protected, has the ability to induce a dramatic reduction in amyloid deposition in two different transgenic Alzheimer's models (Permanne, B., Adessi, C., Saborio, G. P., Fraga, S., Frossard, M.-J., Dewachter, I., Van Dorpe, J., Banks, W. A., Van Leuven, F., and Soto, C. (2002) FASEB J. 16, 860-862). The aim of this study was to evaluate the effect of chemical modifications of the peptide bonds at the metabolite cleavage sites on the pharmacological properties of iA beta 5p derivatives. Using a rational approach, peptide analogs were designed and tested for in vitro activity and enzymatic stability. One peptide analog containing a methyl group introduced at the nitrogen atom of one amide bond showed increased stability in vitro, a 10-fold higher in vivo half-life, and good brain uptake compared with iA beta 5p while maintaining a similar activity in vitro. Our results suggest that the pharmacological profile of beta-sheet breaker peptides can be improved to produce compounds with drug-like properties that might offer a new promise in the treatment of Alzheimer's disease.

Banks WA, Terrell B, Farr SA, Robinson SM, Nonaka N, Morley JE. · GRECC, Division of Geriatrics, Department of Internal Medicine, Veterans Affairs Medical Center-St. Louis and Saint Louis University School of Medicine, St. Louis, MO 63106, USA. · Peptides. · Pubmed #12535702 No free full text.

Abstract: Vaccinations against amyloid beta protein (A beta P) reduce amyloid deposition and reverse learning and memory deficits in mouse models of Alzheimer's disease. This has raised the question of whether circulating antibodies, normally restricted by the blood-brain barrier (BBB), can enter the brain [Nat. Med. 7 (2001) 369-372]. Here, we show that antibody directed against A beta P does cross the BBB at a very low rate. Entry is by way of the extracellular pathways with about 0.11% of an intravenous (i.v.) dose entering the brain by 1h. Clearance of antibody from brain increasingly dominates over time, but antibody is still detectable in brain 72 h after i.v. injection. Uptake and clearance is not altered in mice overexpressing A beta P. This ability to enter and exit the brain even in the presence of increased brain ligand supports the use of antibody in the treatment of Alzheimer's and other diseases of the brain.

Nonaka N, Banks WA, Mizushima H, Shioda S, Morley JE. · Department of Oral Anatomy, Showa University School of Dentistry, Tokyo, Japan. · Peptides. · Pubmed #12535699 No free full text.

Abstract: The blood-brain barrier (BBB) controls the exchange of peptides and regulatory proteins between the central nervous system (CNS) and the blood. Transport across the BBB of such regulatory substances is altered in animal models of Alzheimer's disease. These alterations could lead to cognitive impairments or diminish their therapeutic potential. Here, we measured the transport rate of radioactively labeled pituitary adenylate cyclase-activating polypeptide (PACAP) from blood into whole brain and into 11 brain regions in three groups of mice: young (2 months old) ICR, young (2 months old) SAMP8, and aged (12 months old) SAMP8 mice. The SAMP8 is a strain which develops impaired learning and memory with aging that correlates with an age-related increase in brain levels of amyloid beta protein (A beta P). PACAP is a powerful neurotrophin that may have a therapeutic role in neurodegenerative diseases. We found that I-PACAP crossed the BBB fastest at the hypothalamus and the hippocampus in all three groups. Slower transport rates into the whole brain, the olfactory bulb, the hypothalamus, and the hippocampus for aged SAMP8 mice was likely related to differences both from strain and expression of A beta P with aging.

Permanne B, Adessi C, Saborio GP, Fraga S, Frossard MJ, Van Dorpe J, Dewachter I, Banks WA, Van Leuven F, Soto C. · Serono Pharmaceutical Research Institute, 1228 Geneva, Switzerland. · FASEB J. · Pubmed #11967228 links to  free full text

Abstract: Genetic, neuropathological, and biochemical studies have provided strong evidence for a central role of amyloid in the pathogenesis of Alzheimer's disease (AD). We have proposed previously that peptides designed as beta-sheet breakers may be useful in preventing the formation of amyloid plaques. In this study, we describe a modified beta-sheet breaker peptide with improved pharmacological properties, a high rate of penetration across the blood-brain barrier, and the ability to induce a dramatic reduction in amyloid deposition in two different transgenic AD models. In addition, we report for the first time a significant increase in neuronal survival and a decrease in brain inflammation associated with the reduction of amyloid plaques. These results demonstrate that the process of amyloid deposition is one of the causes of neurodegeneration in AD. Moreover, our findings indicate that beta-sheet breaker peptides provide a valuable tool for evaluating further the importance of amyloid in the etiology of AD and suggest that these peptides or some of their derivatives might be good candidates for AD treatment.

Morley JE, Farr SA, Kumar VB, Banks WA. · Geriatric Research, Education, & Clinical Center (GRECC), VA Medical Center, St. Louis, MO, USA. · Peptides. · Pubmed #11836012 No free full text.

Abstract: There is now ample evidence that beta-amyloid proteins decrease memory. The SAMP8 mouse (P8) develops an early decline in the ability to learn and to retain new information. The studies reviewed here suggest that this is due to overproduction of beta-amyloid. Both antibodies to beta-amyloid and specific antisense to the amyloid precursor protein reverse these deficits in the P8 mouse. This antisense can cross the blood brain barrier. It is hypothesized that the overproduction of beta-amyloid leads to a decline in Delta(9) desaturase activity with an alteration in membrane fatty acids. This results in altered membrane mobility leading to a decline in neurotransmitter activity and a decreased release of acetylcholine. This decreased cholinergic activity results in a decreased ability of the P8 mouse to learn and retain new information.

Banks WA, Moinuddin A, Morley JE. · GRECC, Veterans Affairs Medical Center-St. Louis and Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63106, USA. · Neurobiol Aging. · Pubmed #11445267 No free full text.

Abstract: The blood-brain barrier (BBB) controls the exchange of regulatory substances, including tumor necrosis factor-alpha (TNF), between the brain and the blood. Transport across the BBB of some regulatory substances is altered with aging. Here, we measured the blood to brain unidirectional influx rate (Ki) for whole brain and 10 brain regions for radioactively labeled TNF in three groups of mice: young (2 mo old) ICR (the standard outbred albino laboratory mouse also termed CD-1), young SAMP8 (a strain which develops impaired learning and memory with aging that correlates with an age-related increase in brain levels of amyloid beta protein), and aged (17 mo) SAMP8 mice. In ICR mice, the hypothalamus had the fastest (1.73 microl/g-min) and the parietal cortex the slowest (0.189 microl/g-min) rates of uptake, a regional difference of about 9 fold. No differences in transport into whole brain or brain regions occurred between the ICR and young SAMP8, showing a lack of differences between strains. Transport was higher for the occipital cortex, midbrain, and striatum in aged SAMP8 mice. These results show blood-borne TNF enters some regions of the brain much more readily than others and TNF transport is increased into some brain regions of the SAMP8 mice at an age when learning and memory are impaired.

Banks WA, Farr SA, Butt W, Kumar VB, Franko MW, Morley JE. · Geriatric Research, Education and Clinical Center, St. Louis Veterans Affairs Medical Center and Department of Internal Medicine, Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA. · J Pharmacol Exp Ther. · Pubmed #11356936 links to  free full text

Abstract: Amyloid beta protein (Abeta) may play a causal role in Alzheimer's disease. Previous work has shown that the learning and memory deficits that develop with aging in SAMP8 mice, a strain that overproduces Abeta, can be reversed with i.c.v. injections of an Abeta antisense phosphorothiolate oligonucleotide (Olg). Here, we showed that Olg radioactively labeled with (32)P (P-Olg) was transported intact across the blood-brain barrier (BBB) of mice by a saturable system, termed oligonucleotide transport system-1 (OTS-1). Multiple-time regression analysis found a blood-to-brain unidirectional influx rate for P-Olg of 1.4 +/- 0.39 microl/g-min and capillary depletion showed that P-Olg completely crossed the BBB to enter the parenchymal space of the brain. P-Olg was also shown to enter the cerebrospinal fluid. Transport was especially high into the hippocampus, with the percentage of the i.v. dose taken up by each gram of brain (0.865 +/- 0.115%) being about 1/100 of the i.c.v. dose. An i.v. dose of Olg 100 times that of the effective i.c.v. dose reversed the learning and memory deficits of aged SAMP8 mice. These studies show for the first time that phosphorothiolate oligonucleotides can be delivered to the brain in effective doses by intravenous administration.

Kumar VB, Farr SA, Flood JF, Kamlesh V, Franko M, Banks WA, Morley JE. · Geriatric Research, Education and Clinical Center, St. Louis VA Medical Center, St. Louis, MO, USA. · Peptides. · Pubmed #11150636 No free full text.

Abstract: beta amyloid protein (Abeta) is a 40-43 amino acid peptide derived from amyloid precursor protein (APP). Abeta has been implicated as a cause of Alzheimer's disease (AD). Mice with spontaneous or transgenic overexpression of APP show the histologic hallmarks of AD and have impairments in learning and memory. We tested whether antisense phosphorothiolated oligonucleotides (AO) directed at the Abeta region of the APP gene given with or without antibody directed at Abeta could reverse the elevated protein levels of APP and the behavioral impairments seen in SAMP8 mice, a strain which spontaneously overexpresses APP. We found that intracerebroventricular (ICV) administration of antibody with either of two AOs directed at the midregion of Abeta improved acquisition and retention in a footshock avoidance paradigm, whereas two AOs directed more toward the C-terminal, a random AO, and vehicle were without effect. Three injections of the more potent AO given without antibody reduced APP protein levels by 43-68% in the amygdala, septum, and hippocampus. These results show that AO directed at the Abeta region of APP can reduce APP levels in the brain and reverse deficits in learning and memory.