Neuropathology in Alzheimer's disease: awaking from a hundred-year-old dream

For one hundred years after Alois Alzheimer's first report of Alzheimer's disease (AD) in 1906, the pathological hallmarks of the disease, senile plaques and neurofibrillary tangles (NFTs), have been attractive targets for researchers. Therefore, not surprisingly, efforts to understand disease mechanisms have concentrated on the cell biology of amyloid-beta (Abeta) deposition as senile plaques or on the phosphorylation and aggregation of tau as NFTs. However, it now appears that this focus on pathology as a central contributor to disease may be misguided. Indeed, neurons associated with Abeta and NFTs in AD brain show a decrease in oxidative damage relative to those in vulnerable but morphologically intact areas of the brain, suggesting that neurodegenerative lesions are compensatory phenomena, and thus manifestations of cellular adaptation. That Abeta and tau accumulations indicate an age-related physiological reaction to chronic stress calls into question the rationale of current therapeutic efforts targeted toward lesion removal. Moreover, if this concept holds true for pathology in other neurodegenerative diseases, we may need to restructure our thinking and undergo a paradigm shift before substantial progress can be made in therapeutic intervention.     

Alzheimer's disease

In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with Alzheimer's disease (AD). AD commonly presents with impairment of memory and language function. In this case, language difficulties were noted more prominently than was memory impairment. Throughout the limbic system and neocortex of the patient were large numbers of senile plaques and neurofibrillary tangles, the pathological hallmarks of AD.     

Immune shaping and the development of Alzheimer's disease vaccines

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.     

The development of amyloid beta protein deposits in the aged brain

The deposition of amyloid beta protein (Abeta) in the human brain and the generation of neurofibrillary tangles are the histopathological hallmarks of Alzheimer's disease. Accumulation of Abeta takes place in senile plaques and in cerebrovascular deposits as a result of an imbalance between Abeta production and clearance. This Review describes the different types of Abeta deposits, which can be distinguished by their morphology and by the hierarchical involvement of distinct areas of the brain in Abeta deposition. The role of intracellular Abeta in Abeta deposition and the mechanism of Abeta toxicity are also discussed.     

Can new neurons replace memories lost?

It now appears that new neurons are produced not only in the healthy adult brain but also in the brains of patients with Alzheimer's disease (AD). Although the function of new neurons in the healthy brain is unknown, there is evidence that they are involved in certain types of memory formation and that their survival is enhanced dramatically and persistently by learning experiences. The evidence that neurogenesis, or at least the expression of proteins unique to immature neurons, occurs during the late stages of AD raises the possibility that their production could be enhanced earlier in the disease process before so many neurons and memories are lost.     

Immunotherapy for Alzheimer's disease

Strong evidence exists indicating that chronic neuroinflammation contributes to the progression of Alzheimer's disease (AD). A major focus of AD-associated research has been amyloid-beta (Abeta) protein deposits. Vaccination with Abeta stimulates phagocytosis of Abeta in transgenic mouse models of AD, leading to clearance of the deposits. Similar vaccination in humans with AD has, however, led to meningoencephalitis in some cases. The difference probably depends on the initial level of brain inflammation, which is much higher in bona fide AD in humans than in the transgenic mice. Because both pro- and anti-inflammatory activation of immune cells are possible, stimulating the phagocytic action of microglia while simultaneously stimulating anti-inflammatory activity might be beneficial in AD.     

Plaque attack. Mice without ApoE and related protein unexpectedly accumulate beta-amyloid deposits

A person can toss her wadded-up burger wrapper into either the gutter or a trash bin. New work establishes that ApoE, a protein connected to Alzheimer's disease (AD), makes a similar choice. Mouse studies have suggested that ApoE encourages formation of the beta-amyloid plaques that gum up patients' brains. But scientists now suggest that ApoE helps clear beta amyloid from the brain before it forms plaques. The results warn that targeting ApoE as an AD treatment will require balancing its positive and negative influences.     

Plasticity in Early Alzheimer's Disease: An Opportunity for Intervention

The scientific evidence of plasticity, or the brain's dynamic ability to alter its organization and activation throughout one's lifetime, has increased significantly over the last decade. This analytic review evaluates selected evidence regarding the persistence of plasticity in people with early-stage Alzheimer's disease (AD). Functional neuroimaging provides persuasive evidence of plasticity throughout aging as well as the early stages of dementia, including the possibility of a heightened response during the prodromal period of AD. Behavioral outcomes research demonstrates the ability of people with early-stage AD to relearn previously forgotten information or otherwise improve cognitive abilities following a cognition-focused intervention. Both of these bodies of evidence support the existence of compensatory processes at work, even in the presence of dementia-related pathology. This retained ability of the brain to adapt to neurodegenerative disease in an attempt to maintain function may provide a valuable opportunity for intervention, particularly in the prodromal or earliest stages of AD.     

Androgens, apoE, and Alzheimer's disease

Increasing evidence indicates that there are reductions in estrogen and androgen levels in aged men and women. These hormonal reductions might be risk factors for cognitive impairments and the development of Alzheimer's disease (AD). Aged people show improved cognition after treatments with sex steroids. Therefore, ongoing clinical AD trials have been designed to evaluate the potential benefits of estrogen therapy in women and testosterone therapy in men. Apolipoprotein E (apoE) plays an important role in the metabolism and redistribution of lipoproteins and cholesterol. The three major human apoE isoforms, apoE2, apoE3, and apoE4, differ in their effects on AD risk and pathology. Here I review various mechanisms proposed to mediate the differential effects of apoE isoforms on brain function and highlight the potential contribution of detrimental isoform-dependent effects of apoE on androgen- and androgen receptor (AR)-mediated pathways. I also discuss potential interactions of androgens with other AD-related factors.     

Alzheimer's disease,neuropeptides, neuropeptidase,and amyloid-beta peptide metabolism

Amyloid-beta peptide (Abeta), the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in the brain. We have focused our attention and effort on elucidating the unresolved aspect of Abeta metabolism: proteolytic degradation. Among a number of Abeta-degrading enzyme candidates, we used a novel in vivo paradigm to identify a member of the neutral endopeptidase family, neprilysin, as the major Abeta catabolic enzyme. Neprilysin deficiency results in defects in the metabolism of endogenous Abeta 40 and 42 in a gene dose-dependent manner. Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting Abeta accumulation. Moreover, we discuss the fact that an aging-dependent decline of neprilysin activity, which leads to elevation of Abeta concentrations in the brain, is a natural process that precedes AD pathology. In this Perspective, we hypothesize that neprilysin down-regulation has a role in sporadic AD (SAD) pathogenesis, and we propose that this knowledge be used for developing preventive and therapeutic strategies through use of a G protein-coupled receptor (GPCR).     

Targeting the role of the endosome in the pathophysiology of Alzheimer's disease: a strategy for treatment

Membrane-bound endosomal vesicles play an integral role in multiple cellular events, including protein processing and turnover, and often critically regulate the cell-surface availability of receptors and other plasma membrane proteins in many different cell types. Neurons are no exception, being dependent on endosomal function for housekeeping and synaptic events. Growing evidence suggests a link between neuronal endosomal function and Alzheimer's disease (AD) pathophysiology. Endosomal abnormalities invariably occur within neurons in AD brains, and endocytic compartments are one likely site for the production of the pathogenic beta-amyloid peptide (Abeta), which accumulates within the brain during the disease and is generated by proteolytic processing of the amyloid precursor protein (APP). The enzymes and events involved in APP processing are appealing targets for therapeutic agents aimed at slowing or reversing the pathogenesis of AD. The neuronal endosome may well prove to be the intracellular site of action for inhibitors of beta-amyloidogenic APP processing. We present here the view that knowledge of the endosomal system in the disease can guide drug discovery of AD therapeutic agents.     

Cyclin-dependent kinase 5--a neuronal killer?

In dividing cells, cyclin-dependent kinases (Cdks) are cell cycle-associated protein kinases that regulate proliferation, differentiation, senescence, and apoptosis. In neurons that no longer divide, deregulation of Cdks, especially Cdk5, occurs in many neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Cdk5 is a unique member of the Cdk family because it does not play a critical role in cell cycle progression, and it is not activated by a cyclin. Instead, Cdk5 normally is activated by the regulatory protein p35. This Cdk5/p35 activity has emerged as an important regulator of proper development of the mammalian central nervous system. In vitro studies suggest that aberrant activation of Cdk5 by an endogenous truncated version (p25) of p35 might be a key event in the process of neurodegeneration. One enzyme responsible for cleavage of p35 to form p25 is calpain, a calcium-activated protease that has been shown to be involved in neuronal cell death. Recent studies provided important in vivo evidence that hyperactivation and redistribution of Cdk5 by p25 plays an essential role in the phosphorylation of "pathological" substrates (such as tau) and the cell death of neurons in experimental models of AD and PD. Because amyloid beta peptide, the primary neurotoxic component of amyloid plaques in AD, has been shown to increase the conversion of p35 to p25, aberrant activation of Cdk5 by p25 might be a pathway connecting amyloid beta toxicity to tau hyperphosphorylation in AD.     

Interactions Among Sexual Activity,Menstrual Cycle Phase,and Immune Function in Healthy Women

Past research has found menstrual-cycle-related changes in functional immune response; we examined if sexual activity also changed markers of immune defense. We followed 32 naturally cycling women (15 sexually active with a partner ≥ 1 time/week, 17 sexually abstinent for the last four months) over one menstrual cycle. Participants provided serum and saliva samples at menses and ovulation, and additional saliva samples at midfollicular and midluteal phases. At each phase, participants also self-reported symptoms associated with colds, flu, pain, menstrual discomfort, and premenstrual syndrome. We tested saliva and serum for ability to kill Escherichia coli or Candida albicans, and serum for complement protein activity. For serum-mediated pathogen killing, among sexually active women only, there was a significant midcycle decrease in killing of E. coli. For saliva-mediated pathogen killing, among abstinent women only, there was a significant midcycle decrease in killing of E. coli, and midcycle increase in killing of C. albicans. Sexually active women had significantly lower complement activity than abstinent women overall. Finally, both groups reported lower physical symptoms at midcycle and higher symptoms at menses. There may be important differences in immune function between healthy women who are sexually active versus abstinent. Further replication is warranted.     

Arbiters,Entrepreneurs, and the Shaping of Business School Reputations1

How are organizational reputations established? Expanding on recent work that emphasizes the construction of reputations rather than their cultural content, we explore how forces in the organizational environment define organizational reputation. Specifically, we demonstrate how two types of mediators—reputational arbiters and reputational entrepreneurs—influence the development of reputations by organizing and managing the information on which reputations are built. Buttressing our theoretical claims with 30 interviews of business school administrators, we find that these mediators play a central role in determining organizational reputations by engaging in three processes of information manipulation: synthesis, selection, and simplification. In addition to specifying the key role that the manipulation of information by outsiders plays in the development of reputation, this approach suggests the importance of the interrelationships among these mediators in the determination of reputational standing.     

Mutual Interests,Different Lenses: Current Neuroscience and Symbolic Interaction

As reflective thinkers, symbolic interactionists may well be curious about the organ with which we think. Leading neuroscientists are quite aware that a working brain depends on other brains. This article considers selected neuroscience approaches to topics traditionally addressed by symbolic interactionists including some confirmations, refinements, and challenges from current neuroscience. Confirmations support features of Mead's “objective reality of perspectives” and a relational epistemology, the inevitability of ad hoc “accounts,” self‐consciousness as behavioral control, and “self unity” as constantly re‐created illusion. Divergence between neuroscience and symbolic interaction mainly involves new evidence for the importance of unconscious cognition, emotion, and memory in shaping human behavior. The rooting of cognitive and perceptual processes in motor activity challenges the extremes of the “linguistic turn.” Refinement involves reasons for attending to the embodied salience of thoughts produced by “somatic markers” rather than mere content.     

Shake,Rattle, and … One or Two Objects? Young Infants' Use of Auditory Information to Individuate Objects

Most research on object individuation in infants has focused on the visual domain. Yet the problem of object individuation is not unique to the visual system, but shared by other sensory modalities. This research examined 4.5‐month‐old infants' capacity to use auditory information to individuate objects. Infants were presented with events in which they heard 2 distinct sounds, separated by a temporal gap, emanate from behind a wide screen; the screen was then lowered to reveal 1 or 2 objects. Longer looking to the 1‐ than 2‐object display was taken as evidence that the infants (a) interpreted the auditory event as involving 2 objects and (b) found the presence of only 1 object when the screen was lowered unexpected. The results indicated that the infants used sounds produced by rattles, but not sounds produced by an electronic keyboard, as the basis for object individuation (Experiments 1 and 2). Data collected with adult participants revealed that adults are also more sensitive to rattle sounds than electronic tones. A final experiment assessed conditions under which young infants attend to rattle sounds (Experiment 3). Collectively, the outcomes of these experiments suggest that infants and adults are more likely to use some sounds than others as the basis for individuating objects. We propose that these results reflect a processing bias to attend to sounds that reveal something about the physical properties of an object—sounds that are obviously linked to object structure—when determining object identity.     

Asian Americans and Alzheimer's disease: Assimilation,culture, and beliefs

Because most successful interventions for Alzheimer's disease (AD) rely upon early diagnosis and implementation, it is important to understand the factors influencing dementia treatment-seeking behaviors. These include perceptions, beliefs, values, and feelings relating to AD, which may vary among and within ethnic groups according to the strength of culturally-based explanatory models and individual group members' ages and experiences. This study used ten focus groups drawn from Asian American communities representing different national origins (Chinese, Japanese, and Korean) to examine the factors shaping attitudes toward AD in general, and treatment-seeking in particular, that may constitute barriers to timely diagnosis and treatment of AD among Asian Americans of various ages and cultural backgrounds. The results suggest that, while these communities share a keen awareness of AD, beliefs regarding the disorder may be influenced at least as strongly by folk wisdom and culturally acceptable partial truths as by scientific information.     

Unemployment,immigration, and NAFTA: a panel study of ten major U.S. industries

We conduct a pooled cross-section and time-series analysis of the unemployment rates across ten major industries in the U.S. from 1983 to 1994 to assess the effect of NAFTA and immigration. Our results indicate that the output produced by the industry, unemployment benefit coverage, and interest rates are significant determinants of industry unemployment rates, but union presence does not affect industry unemployment. Both Canadian and Mexican immigrants appear to be complements to the U.S. labor force, with Canadian immigrants highly complementary to American labor. Finally, the Chow test provides no evidence that NAFTA has changed the structure of unemployment determination in these industries. We are indebted to Emily Hoffman and Matthew Higgins for their comments and suggestions. The usual disclaimer applies.     

Modularity in philosophy, the neurosciences, and psychiatry

The neurosciences are generating new findings regarding genetic and neurobiological aspects of the pathophysiology of mental disorders. Especially, certain genetic risk factors like neuregulin-1 seem to predispose individuals to a psychotic phenotype beyond the limits of traditional classificatory boundaries between organic psychoses in Alzheimer’s disease, bipolar affective disorder and schizophrenia. Little, however, is known about how such genetic risk factors actually confer an increased risk for psychosis in an individual patient. A gap between neuroscientific findings and psychopathological phenomena exists. The main hypothesis how this gap may be bridged is that mental disorders arise as a consequence of dysfunctions of normal mental functions. Modularity may provide a useful conceptual framework in that temporally and/or spatially stable neural circuits subserve certain physiological functions of the human brain, which become the target of pathophysiological effectors. The idea of a modular construction of the human brain is based on neurobiological evidence regarding the columnar architecture of the cerebral cortex, which provides certain elementary analytical functions. Modular dysfunctions may be assessed with methods of experimental psychopathology, in which subsystems of brain functions are tested with standardized experimental psychological techniques (functional psychopathology). The main questions here are how to define a module, and whether the classical neuroscientific definitions can be used to characterize higher integrative functions of the human brain.     

THE HAZARDOUS EFFECTS OF ANTIDUMPING

We investigate the extent to which antidumping actions eliminate trade altogether. Using quarterly 10‐digit HS‐level export data for products involved in U.S. antidumping cases we find that antidumping actions increase the hazard rate by more than 50%. We find strong evidence of investigation effects with the impact during the initiation and preliminary duty phases considerably larger than once final duties are imposed. There are also important differences with respect to the size of duties with cases with large duties experiencing very large investigation effects. We show the antidumping (AD)‐affected countries are less likely to return to the market even after the AD order is removed. (JEL F13, F14)