The readings listed below are the foundation of this course. Where available, journal article abstracts from
PubMed (an online database providing access to citations from biomedical literature) are included.
Reading List
Abrisquita-Gomez, et al. "Recognition memory for emotional pictures in Alzheimer's patients." Acta Neurologica Scandinavica 105 (2002): 51-54.
Baddeley, A. D., S. Bressi, S. Della Sala, R. Logie, and H. Spinnler. "The decline of working memory in Alzheimer's disease." Brain 114 (1991): 2521-2542.
PubMed abstract: A previous study (Baddeley et al., 1986) explored the hypothesis that patients suffering from dementia of the Alzheimer type (AD) are particularly impaired in the functioning of the central executive component of working memory. It showed that, when patients are required to perform 2 concurrent tasks simultaneously, the AD patients are particularly impaired, even when level of performance on the individual tasks is equated with that of age-matched controls. Although the results were clear, interpretation was still complicated by 2 issues: first, the question of comparability of performance on the separate tests between AD and control patients; secondly, the question of whether our results could be interpreted simply in terms of a limited general processing capacity being more taxed by more difficult dual tasks than by the individual tasks performed alone. The present study followed up the AD and control patients after 6 and 12 mths. We were able to allow for the problem of comparability of performance by using patients as their own control. Under these conditions, there is a very clear tendency for dual task performance to deteriorate while single task performance is maintained. A second experiment varied difficulty within a single task in which patients and controls were required to categorize words as belonging to 1, 2 or 4 semantic categories. There was a clear effect of number of categories on performance and a systematic decline in performance over time. There was, however, no interaction between task difficulty as measured by number of alternatives and rate of deterioration, suggesting that the progressive deterioration in performance shown by AD patients is a function of whether single or dual task performance is required, and is not dependent on simple level of task difficulty. Implications for the analysis of the central executive component of working memory are discussed.
Baddeley, A. D. "Working memory." Science 255 (1992): 556-559.
PubMed abstract: The term working memory refers to a brain system that provides temporary storage and manipulation of the information necessary for such complex cognitive tasks as language comprehension, learning, and reasoning. This definition has evolved from the concept of a unitary short-term memory system. Working memory has been found to require the simultaneous storage and processing of information. It can be divided into the following three subcomponents: (i) the central executive, which is assumed to be an attentional-controlling system, is important in skills such as chess playing and is particularly susceptible to the effects of Alzheimer's disease; and two slave systems, namely (ii) the visuospatial sketch pad, which manipulates visual images and (iii) the phonological loop, which stores and rehearses speech-based information and is necessary for the acquisition of both native and second-language vocabulary.
Craik, F. I. M., and J. McDowd. "Age differences in recall and recognition." Journal of Experimental Psychology: Learning, Memory and Cognition 13(3) (1987): 474-479.
Glenner, G. G. "Amyloid beta protein and the basis for Alzheimer's disease." Prog Clin Biol Res. 317 (1989): 857-68.
PubMed abstract: The amyloid fibril protein isolated from the cerebrovascular amyloid deposits seen in 92% of cases of Alzheimer's disease and 100% of cases of Down's syndrome over the age of 40 has been shown to have a previously unknown amino acid sequence. This protein has been designated beta protein (beta P) and the type amyloid fibrils, ACv beta. Polyclonal and monoclonal antibodies raised to a synthetic peptide comprising the first 10 amino acids of beta P localized both to cerebrovascular amyloid deposits as well as to the amyloid cores of all "senile" plaques. An amino acid sequence analysis based on that of the beta P has been reported indicating that the plaque amyloid fibril deposits are also composed of beta P. These deposits must cause severe disruption of neuronal fibers. Thus beta P in the form of amyloid deposits seems intrinsic to the destruction of neuronal competence and thus to the ensuing dementia of Alzheimer's disease. Since proteolysis converts the beta P precursor (Pre beta P) into amyloid fibrils, it is possible that 1) an abnormality in synthesis of the Pre beta P, perhaps during post-transitional events, or 2) an abnormality in proteolytic processing occurs to afford beta P deposits and the pathologic changes in Alzheimer's disease. Regardless of the processing abnormality, beta P represents a major component in the pathogenesis of Alzheimer's disease.
Glenner, G. G., and C. W. Wong. "Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein." Biochem Biophys Res Commun. 122(3) (1984): 1131-5.
PubMed abstract: The cerebrovascular amyloid protein from a case of adult Down's syndrome was isolated and purified. Amino acid sequence analysis showed it to be homologous to that of the beta protein of Alzheimer's disease. This is the first chemical evidence of a relationship between Down's syndrome and Alzheimer's disease. It suggests that Down's syndrome may be a predictable model for Alzheimer's disease. Assuming the beta protein is a human gene product, it also suggests that the genetic defect in Alzheimer's disease is localized on chromosome 21.
Glisky, E., et al. "Source memory in older adults: An encoding or retrieval problem?" Journal of Experimental Psychology: Learning, Memory and Cognition 27(5) (2001): 1131-1146.
PubMed abstract: Source memory has been found to be more affected by aging than item memory, possibly because of declining frontal function among older adults. In 4 experiments, the authors explored the role of the frontal lobes (FLs) in source memory, the extent to which they may be involved in the encoding and/or retrieval of source or context, and the conditions under which the source memory deficit in older people may be reduced or eliminated. Results indicated that only a subset of older adults show deficits in source memory, namely those with below average frontal function, and these deficits can be eliminated by requiring people at study to consider the relation between an item and its context. These results provide convincing evidence of the importance of frontal function during the encoding of source and suggest that older adults with reduced FL function fail to initiate the processes required to integrate contextual information with focal content during study.
Hamann, et al. "Impaired fear conditioning in Alzheimer's disease." Neuropsychologia 40 (2002): 1187-1195.
PubMed abstract: Classical conditioning of the fear response is a basic form of nondeclarative (nonconscious) memory that mediates both normal and pathological responses to aversive stimuli. Because fear conditioning critically depends on the amygdala, a medial temporal lobe structure that frequently undergoes significant pathological changes early in the course of Alzheimer's disease (AD), we hypothesized that fear conditioning would be impaired in patients with mild to moderate AD. We examined simple classical fear conditioning in a group of 10 patients with probable AD and 14 demographically matched, neurologically intact elderly controls. During conditioning, one stimulus (e.g. a green rectangle, the conditioned stimulus (CS+)), was paired with an aversive stimulus (a loud noise, the unconditioned stimulus (US)) using a partial reinforcement conditioning schedule. The opponent color (e.g. red rectangle), the CS-, was never paired with the US. The elderly controls acquired robust fear responses as demonstrated by their differential skin-conductance responses to the CS+ and CS-. In contrast, the AD group showed a marked impairment in conditioning, failing to exhibit significant conditioned fear responses. This failure to acquire conditioned responses could not be attributed to diminished responding by patients, relative to controls, to the aversive US. The results indicate that fear conditioning, an amygdala-dependent form of memory, is impaired in AD. These findings complement previous reports of impairments in declarative emotional memory in AD by demonstrating that a basic form of nondeclarative emotional memory is also impaired in AD.
Head, D., N. Raz, F. Gunning-Dizxon, A. Williamson, and J. D. Acker. "Age-related differences in the course or cognitive skill acquisition: the role of regional cortical shrinkage and cognitive resources." Psychology and Aging 17 (2002): 72-84.
PubMed abstract: This study examined the impact of age-related differences in regional cerebral volumes and cognitive resources on acquisition of a cognitive skill. Volumes of brain regions were measured on magnetic resonance images of healthy adults (aged 22-80). At the early stage of learning to solve the Tower of Hanoi puzzle, speed and efficiency were associated with age, prefrontal cortex volume, and working memory. A similar pattern of brain-behavior associations was observed with perseveration measured on the Wisconsin Card Sorting Test. None of the examined structural brain variables were important at the later stages of skill acquisition. When hypertensive participants were excluded, the effect of prefrontal shrinkage on executive aspects of performance was no longer significant, but the effect of working memory remained.
Irizarry, C., and B. Hyman. "Alzheimer disease therapeutics." Journal of Neuropathology and Experimental Neurology 60(10) (2001): 923-928.
PubMed abstract: Alzheimer disease (AD) is characterized pathologically by cholinergic deficits, amyloid plaques, neurofibrillary tangles, gliosis, and neuronal and synaptic loss. The primary therapeutic approach that has arisen from the pathological analysis of AD brain has been cholinergic augmentation by cholinesterase inhibitors, which modestly improve cognitive function. Research on the underlying pathophysiological dysfunction have focussed on AD-specific processes such as amyloid precursor protein, tau, and cerebral apolipoprotein E metabolism, and more general neurodegenerative processes such as inflammation, oxidation, excitotoxicity, and apoptosis. Rational neuroprotective approaches have led to recent trials of estrogen, antioxidant and anti-inflammatory medications in AD, and to the development of anti-amyloid strategies for delaying progression or preventing development of AD.
Jonides, J., C. Marshuetz, E. E. Smith, E. E. Reuter-Lorenz, and A. Hartley. "Age differences in behavior and PET activation reveal differences in interference resolution in verbal working memory." Journal of Cognitive Neuroscience 12 (2000): 188-196.
PubMed abstract: Older adults were tested on a verbal working memory task that used the item-recognition paradigm. On some trials of this task, response-conflict was created by presenting test-items that were familiar but were not members of a current set of items stored in memory. These items required a negative response, but their familiarity biased subjects toward a positive response. Younger subjects show an interference effect on such trials, and this interference is accompanied by activation of a region of left lateral prefrontal cortex. However, there has been no evidence that the activation in this region is causally related to the interference that the subjects exhibit. In the present study, we demonstrate that older adults show more behavioral interference than younger subjects on this task, and they also show no reliable activation at the same lateral prefrontal site. This leads to the conclusion that this prefrontal site is functionally involved in mediating resolution among conflicting responses or among conflicting representations in working memory.
Kensinger, E., and S. Corkin. "Cognition in aging and age-related disease." In Encyclopedia of Neuroscience. Edited by G. Adelman. (in press).
------. "Alzheimer disease." In Encylcopedia of Cognitive Science. Edited by L. Nadel. UK: Nature Publishing Group, 2003, 83-89.
------. "Neural changes in aging." In Encylcopedia of Cognitive Science. Edited by L. Nadel. UK: Nature Publishing Group, 2003, 70-78.
Kensinger, E. A., D. K. Shearer, J. J. Locascio, J. H. Growdon, and S. Corkin. "Working memory in mild Alzheimer's disease and early Parkinson's disease." Neuropsychology. (in press).
PubMed abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) impair working memory (WM). It is unclear, however, whether the deficits seen early in the course of these diseases are similar. To address this issue, the authors compared the performance of 22 patients with mild AD, 20 patients with early PD and without dementia, and 112 control participants on tests of inhibition, short-term memory, and 2 commonly administered tests of WM. The results suggest that although mild AD and early PD both impair WM, the deficits may be related to the interruption of different processes that contribute to WM performance. Early PD disrupted inhibitory processes, whereas mild AD did not. The WM deficits seen in patients with AD may be secondary to deficits in other cognitive capacities, including semantic memory.
Naveh-Benjamin, M. "Adult age differences in memory performance: Tests of an associative deficit analysis." Journal of Experimental Psychology: Learning, Memory and Cognition 26(5) (2000): 1170-1187.
PubMed abstract: An associative hypothesis to explain and predict older adults' deficient explicit episodic memory performance was outlined and tested. The hypothesis attributes a substantial part of older adults' deficient memory performance to their difficulty in merging unrelated attributes-units of an episode into a cohesive unit. Although each of the components can be memorized to a reasonable degree, the associations that tie the attributes-units to each other grow weaker in old age. Four experiments are reported that provide (a) a converging validity to the hypothesis by demonstrating this associative deficit for both interitem relationships and intraitem relationships and (b) a discriminant validity to the hypothesis by contrasting and testing competing predictions made by the associative hypothesis and by alternative hypotheses. The implications of these results to older adults' episodic memory performance are discussed.
Reuter-Lorenz, P. "New visions of the aging mind and brain." Trends in Cognitive Sciences 6(9) (2002): 394-400.
PubMed abstract: Cognitive aging is widely viewed as a process of progressive mental loss. Compelling new evidence from functional neuroimaging urges a reconsideration of this pessimistic view. In the domains of working memory and episodic memory, older adults recruit different brain regions from those recruited by younger adults when performing the same tasks. Specifically, older adults show prominent changes in the recruitment of prefrontal regions, and a conspicuous increase in the extent to which activation patterns are bilateral. These results are stimulating new hypotheses about the mechanisms underlying age-related cognitive declines and the potential for compensation. By suggesting a life-long potential for reorganization and plasticity, these discoveries might revise long-held views of functional localization.
Rypma, B., V. Prabhakaran, J. E. Desmond, and J. D. Gabrieli. "Age differences in prefrontal cortical activity in working memory." Psychology and Aging 16 (2001): 371-384.
PubMed abstract: Working memory (WM) declines with advancing age. Brain imaging studies indicate that ventral prefrontal cortex (PFC) is active when information is retained in WM and that dorsal PFC is further activated for retention of large amounts of information. The authors examined the effect of aging on activation in specific PFC regions during WM performance. Six younger and 6 older adults performed a task in which, on each trial, they (a) encoded a 1- or 6-letter memory set, (b) maintained these letters over 5-s. and (c) determined whether or not a probe letter was part of the memory set. Comparisons of activation between the 1- and 6-letter conditions indicated age-equivalent ventral PFC activation. Younger adults showed greater dorsal PFC activation than older adults. Older adults showed greater rostral PFC activation than younger adults. Aging may affect dorsal PFC brain regions that are important for WM executive components.
Salthouse, T. "The aging of working memory." Neuropsychology 8 (1994): 535-543.
Selkoe. "Part 1: Causes; Current Treatments." 545-552
Selkoe. "Part 2: Inhibition of ß-Secretase." 552-556.
Selkoe, D. J., and D. Schenk. "Alzheimer's Disease: Molecular Understanding predicts Amyloid-based Therapeutics." Annu Rev Pharmacol Toxicol. 43(2003): 545-84.
Tessitore, et al. "Dopamine modulates the response of the human amygdala: a study in Parkinson's disease." Journal of Neuroscience 22(20) (1991): 9099-9103.
PubMed abstract: In addition to classic motor signs and symptoms, Parkinson's disease (PD) is characterized by neuropsychological and emotional deficits, including a blunted emotional response. In the present study, we explored both the neural basis of abnormal emotional behavior in PD and the physiological effects of dopaminergic therapy on the response of the amygdala, a central structure in emotion processing. PD patients and matched normal controls (NCs) were studied with blood oxygenation level-dependent functional magnetic resonance imaging during a paradigm that involved perceptual processing of fearful stimuli. PD patients were studied twice, once during a relatively hypodopaminergic state (i.e., > or =12 hr after their last dose of dopamimetic treatment) and again during a dopamine-replete state. The imaging data revealed a robust bilateral amygdala response in NCs that was absent in PD patients during the hypodopaminergic state. Dopamine repletion partially restored this response in PD patients. Our results demonstrate an abnormal amygdala response in PD that may underlie the emotional deficits accompanying the disease. Furthermore, consistent with findings in experimental animal paradigms, our results provide in vivo evidence of the role of dopamine in modulating the response of the amygdala to sensory information in human subjects.
Please present a short synopsis of:
Bard, F., C. Cannon, R. Barbour, R. L. Burke, D. Games, H. Grajeda, T. Guido, K. Hu, J. Huang, et al. "Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease." Nat Med 6(8) (2000): 916-9.
PubMed abstract: One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.
Blanchard, B. J., A. E. Hiniker, C. C. Lu, Y. Margolin, A. S. Yu, and V. M. Ingram. "Elimination of Amyloid beta Neurotoxicity." J Alzheimers Dis. 2(2) (2000): 137-149.
PubMed abstract: Aggregation of the Alzheimer amyloid beta peptide (Abeta) Abeta1-42 forms neurotoxic fibrils. In contact with human neurons the fibrils cause rapid influx of external calcium through AMPA/kainate-channels. If this molecular mechanism reflects in vivo events, it could explain the pathogenesis of Alzheimer's disease; activation of AMPA/kainate channels is therefore a likely target for therapeutic intervention. Here we show that short antagonistic "decoy peptides", made of D-amino acids, eliminate this "calcium effect" of Ab1-42. Since chronically elevated calcium levels in the disease trigger activation of pathways that lead to neuron dysfunction and cell death, our decoy peptides are obvious candidates for drug development.
Blanchard, B. J., G. Konopka, M. Russell, and V. M. Ingram. "Mechanism and prevention of neurotoxicity caused by beta-amyloid peptides: relation to Alzheimer's disease." Brain Res. 776(1-2) (1997): 40-50.
PubMed abstract: In Alzheimer's disease, neurotoxic beta-amyloid peptides cause a deleterious influx of calcium ions into neurons. This increase in [Ca2+]int is expected to trigger intracellular events that eventually cause cell dysfunction and cell death. We find that the aggregated beta-amyloid peptide beta AP25-35 opens irreversibly a Ca(2+)-carrying channel, as does aggregated beta AP1-42. The opening of this channel is unaffected by DL-AP5, but it is blocked by Mg2+, CNQX and DNQX, suggesting a non-NMDA channel. External calcium enters and cytosolic calcium levels rise several-fold, as measured by fura-2 ratiometric analysis. Our findings illustrate a very early molecular event in the neurotoxicity of Alzheimer's disease. To combat the neurotoxic effect of aggregated beta-amyloid peptides, we have devised a series of very short antagonistic peptides. Using a combinatorial library of hexapeptides made from D-amino acids, we have selected peptides by their ability to complex with the tagged beta-amyloid peptide beta AP25-35. Certain of these so-called 'decoy peptides', as well as some modified decoy peptides, are able to abolish the calcium influx caused by aggregated, probably fibrillar, beta-amyloid peptides beta AP25-35 and beta AP1-42.
Citron, M., T. Oltersdorf, C. Haass, L. McConlogue, A. Y. Hung, P. Seubert, C. Vigo-Pelfrey, I. Lieberburg, and D. J. Selkoe. "Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production." Nature 360(6405) (1992): 672-4.
PubMed abstract: Progressive cerebral deposition of the 39-43-amino-acid amyloid beta-protein (A beta) is an invariant feature of Alzheimer's disease which precedes symptoms of dementia by years or decades. The only specific molecular defects that cause Alzheimer's disease which have been identified so far are missense mutations in the gene encoding the beta-amyloid precursor protein (beta-APP) in certain families with an autosomal dominant form of the disease (familial Alzheimer's disease, or FAD). These mutations are located within or immediately flanking the A beta region of beta-APP, but the mechanism by which they cause the pathological phenotype of early and accelerated A beta deposition is unknown. Here we report that cultured cells which express a beta-APP complementary DNA bearing a double mutation (Lys to Asn at residue 595 plus Met to Leu at position 596) found in a Swedish FAD family produce approximately 6-8-fold more A beta than cells expressing normal beta-APP. The Met 596 to Leu mutation is principally responsible for the increase. These data establish a direct link between a FAD genotype and the clinicopathological phenotype. Further, they confirm the relevance of the continuous A beta production by cultured cells for elucidating the fundamental mechanism of Alzheimer's disease.
Hartley, D. M., D. M. Walsh, C. P. Ye, T. Diehl, S. Vasquez, P. M. Vassilev, D. B. Teplow, and D. J. Selkoe. "Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons." J Neurosci 19(20) (1999): 8876-84.
PubMed abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is thought to be caused in part by the age-related accumulation of amyloid beta-protein (Abeta). The presence of neuritic plaques containing abundant Abeta-derived amyloid fibrils in AD brain tissue supports the concept that fibril accumulation per se underlies neuronal dysfunction in AD. Recent observations have begun to challenge this assumption by suggesting that earlier Abeta assemblies formed during the process of fibrillogenesis may also play a role in AD pathogenesis. Here, we present the novel finding that protofibrils (PF), metastable intermediates in amyloid fibril formation, can alter the electrical activity of neurons and cause neuronal loss. Both low molecular weight Abeta (LMW Abeta) and PF reproducibly induced toxicity in mixed brain cultures in a time- and concentration-dependent manner. No increase in fibril formation during the course of the experiments was observed by either Congo red binding or electron microscopy, suggesting that the neurotoxicity of LMW Abeta and PF cannot be explained by conversion to fibrils. Importantly, protofibrils, but not LMW Abeta, produced a rapid increase in EPSPs, action potentials, and membrane depolarizations. These data suggest that PF have inherent biological activity similar to that of mature fibrils. Our results raise the possibility that the preclinical and early clinical progression of AD is driven in part by the accumulation of specific Abeta assembly intermediates formed during the process of fibrillogenesis.
Morgan, D., et al. "A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease." Nature 408(6815) (2000): 982-5.
PubMed abstract: Vaccinations with amyloid-beta peptide (A beta) can dramatically reduce amyloid deposition in a transgenic mouse model of Alzheimer's disease. To determine if the vaccinations had deleterious or beneficial functional consequences, we tested eight months of A beta vaccination in a different transgenic model for Alzheimer's disease in which mice develop learning deficits as amyloid accumulates. Here we show that vaccination with A beta protects transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer's disease. During testing for potential deleterious effects of the vaccine, all mice performed superbly on the radial-arm water-maze test of working memory. Later, at an age when untreated transgenic mice show memory deficits, the A beta-vaccinated transgenic mice showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as nontransgenic mice. The A beta-vaccinated mice also had a partial reduction in amyloid burden at the end of the study. This therapeutic approach may thus prevent and, possibly, treat Alzheimer's dementia.
Schenk, D., et al. "Immunization with amyloid-beta attenuates Alzheimerdisease- like pathology in the PDAPP mouse." Nature 400(6740) (1999): 173-7.
PubMed abstract: Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.
Selkoe. "Part 3: Inhibition of beta-Secretase." 556-564.
Selkoe. "Part 4: Immunological Approach to Therapy." 564-571.
Selkoe. "Part 5: Other Approaches to Therapy." 571-576.
Sherrington, R., E. I. Rogaev, Y. Liang, E. A. Rogaeva, G. Levesque, M. Ikeda, H. Chi, C. Lin, G. Li, K. Holman, et al. "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease." Nature 375(6534) (1995 ): 754-60.
PubMed abstract: Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.
Walsh, D. M., I. Klyubin, J. V. Fadeeva, W. K. Cullen, R. Anwyl, M. S. Wolfe, M. J. Rowan, and D. J. Selkoe. "Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo." Nature 416(6880) (2002): 535-9.
PubMed abstract: Although extensive data support a central pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Abeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Abeta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Abeta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Abeta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Abeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Abeta oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic Abeta oligomers can be targeted therapeutically.
Yan, R., P. Han, H. Miao, P. Greengard, and H. Xu. "The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta-amyloid precursor protein (APP) substrate." J Biol Chem. 276(39) (2001) : 36788-96.
PubMed abstract: Release of Abeta peptides from beta-amyloid precursor protein (APP) requires sequential cleavage by two endopeptidases, beta- and gamma-secretases. beta-Secretase was recently identified as a novel membrane-bound aspartyl protease, named BACE1, Asp2, or memapsin 2. Employing confocal microscopy and subcellular fractionation, we have found that BACE1 is largely situated in the distal Golgi membrane with a minor presence in the endoplasmic reticulum, endosomes, and plasma membrane in human neuroblastoma SHEP cells and in mouse Neuro-2a cell lines expressing either endogenous mouse BACE1 or additional exogenous human BACE1. The major cellular beta-secretase activity is located in the late Golgi apparatus, consistent with its cellular localization. Furthermore, we demonstrate that the single transmembrane domain of BACE1 alone determines the retention of BACE1 to the Golgi compartments, through examination of recombinant proteins of various BACE1 fragments fused to a reporter green fluorescence protein. In addition, we show that the transmembrane domain of BACE1 is required for the access of BACE1 enzymatic activity to the cellular APP substrate and hence for the optimal generation of the C-terminal fragment of APP (CTF99). The results suggest a molecular and cell biological mechanism for the regulation of beta-secretase activity in vivo.