Showing papers on "Aging brain published in 2000"

Inhibition of the ubiquitin-proteasome system in Alzheimer's disease.

Abstract: Alzheimer's disease is the most common cause of dementia in the elderly. Although several genetic defects have been identified in patients with a family history of this disease, the majority of cases involve individuals with no known genetic predisposition. A mutant form of ubiquitin, termed Ub(+1), has been selectively observed in the brains of Alzheimer's patients, including those with nonfamilial Alzheimer's disease, but it has been unclear why Ub(+1) expression should be deleterious. Here we show that Ub(+1) is an efficient substrate for polyubiquitination in vitro and in transfected human cells. The resulting polyubiquitin chains are refractory to disassembly by deubiquitinating enzymes and potently inhibit the degradation of a polyubiquitinated substrate by purified 26S proteasomes. Thus, expression of Ub(+1) in aging brain could result in dominant inhibition of the Ub-proteasome system, leading to neuropathologic consequences.

Putative role of neuronal 5-lipoxygenase in an aging brain

Abstract: Aging is associated with increased incidence and/or severity of neurodegenerative pathologies. Oxygen-mediated events are being considered as possible mechanisms responsible for the increasing neuronal vulnerability. Lipoxygenases are enzymes that, as cyclooxygenases (COX), can insert oxygen into the molecule of arachidonic acid and thereby synthesize inflammatory eicosanoids: leukotrienes [due to 5-lipoxygenase (5-LOX) activity] and prostaglandins (via COX activity). It appears that 5-LOX is expressed in central nervous system neurons and may participate in neurodegeneration. 5-LOX-triggered cell death may be initiated by the enzymatic activity of 5-LOX but could also occur via the nonenzymatic actions of the 5-LOX protein; new data point to the possibility that 5-LOX protein exerts actions such as interaction with tyrosine kinase receptors, cytoskeletal proteins, and the nucleus. The expression of neuronal 5-LOX is susceptible to hormonal regulation, presumably due to the presence of hormone-responsive elements in the structure of the 5-LOX gene promoter. The expression of the 5-LOX gene and the activity of the 5-LOX pathway are increased in elderly subjects. One possible mechanism of such 5-LOX up-regulation implies the contribution of aging-associated hormonal changes: relative melatonin deficiency and/or hyperglucocorticoidemia. Thus, the 5-LOX pathway could become a promising target of neuroprotective therapies for the aging brain.

Aging Increased Amyloid Peptide and Caused Amyloid Plaques in Brain of Old APP/V717I Transgenic Mice by a Different Mechanism than Mutant Presenilin1

Abstract: Aging of transgenic mice that overexpress the London mutant of amyloid precursor protein (APP/V717I) (Moechars et al, 1999a) was now demonstrated not to affect the normalized levels of aor b-cleaved secreted APP nor of the b-C-terminal stubs This indicated that aging did not markedly disturb either a -o r b-secretase cleavage of APP and failed to explain the origin of the massive amounts of amyloid peptides Ab40 and Ab42, soluble and precipitated as amyloid plaques in the brain of old APP/V717I transgenic mice We tested the hypothesis that aging acted on presenilin1 (PS1) to affect g-secretase-mediated production of amyloid peptides by comparing aged APP/V717I transgenic mice to double transgenic mice coexpressing human PS1 and APP/V717I In double transgenic mice with mutant (A246E) but not wild-type human PS1, brain amyloid peptide levels increased and resulted in amyloid plaques when the mice were only 6‐9 months old, much earlier than in APP/V717I transgenic mice (12‐15 months old) Mutant PS1 increased mainly brain Ab42 levels, whereas in aged APP/V717I transgenic mice, both Ab42 and Ab40 increased This resulted in a dramatic difference in the Ab42/Ab40 ratio of precipitated or plaqueassociated amyloid peptides, ie, 311 6 022 in double APP/ V717I 3 PS1/A246E transgenic mice compared with 043 6 007 in aged APP/V717I transgenic mice, and demonstrated a clear difference between the effect of aging and the effect of the insertion of a mutant PS1 transgene In conclusion, we demonstrate that aging did not favor amyloidogenic over nonamyloidogenic processing of APP, nor did it exert a mutant PS1-like effect on g-secretase Therefore, the data are interpreted to suggest that parenchymal and vascular accumulation of amyloid in aging brain resulted from failure to clear the amyloid peptides rather than from increased production

Critically attained threshold of cerebral hypoperfusion: can it cause Alzheimer's disease?

Abstract: After nearly a century of inquiry, the cause of sporadic Alzheimer's disease (AD) remains to be found. On the subject of AD pathogenesis, recent basic and clinical evidence strongly argues in favor of the concept that AD is linked to brain circulatory pathology. This concept, when viewed from many different medical disciplines and from close pre-morbid similarities to vascular dementia, assembles and hypothetically explains most of the key pathologic events associated with the development of AD. These pathologic events are triggered in AD by impaired cerebral perfusion originating in the microvasculature which affects the optimal delivery of glucose and oxygen and results in an energy metabolic breakdown of brain cell biosynthetic and synaptic pathways. We propose that two factors converge to initiate cognitive dysfunction and neurodegeneration as expressed in AD brain: (1) advanced aging, and (2) the presence of a condition that lowers cerebral perfusion. The first factor introduces a normal but potentially deconstructing process that lowers cerebral blood flow in proportion to increased aging, whereas the second factor adds a crucial burden that further lowers brain perfusion to a critical threshold that triggers neuronal metabolic compromise. When age and a condition that lowers cerebral perfusion converge, critically attained threshold of cerebral hypoperfusion (CATCH) results. CATCH is a cyclical and progressive cerebrovascular insufficiency that will destabilize neurons, synapses, neurotransmission, and cognitive ability, eventually evolving into a neurodegenerative process characterized by the formation of senile plaques, neurofibrillary tangles, and amyloid angiopathy. The concept of impaired cerebral perfusion as the cause of this dementia also explains the heterogeneic profile observed in AD patients, because an extensive list of risk factors for AD are also reported to significantly diminish blood flow to the aging brain.

Partial hippocampal inactivation: effects on spatial memory performance in aged and young rats.

Abstract: Changes in anatomical or functional connectivity during normal aging are thought to contribute to cognitive alterations over the lifespan. Neural network theories predict that synaptic loss in an aging brain could place the organism near the point of dysfunction in the nonlinear curve defining neural compromise versus performance. The present experiments examined whether aged rats are closer to this point of behavioral dysfunction by reversibly inactivating one or both hippocampal hemispheres. As expected, bilateral tetracaine inactivation of the hippocampus disrupted spatial memory in both age groups. Unilateral left hippocampal inactivation significantly increased errors only in aged rats; however, unilateral inactivation of the right hippocampus had no effect. The present outcome could reflect more extensive synaptic dysfunction in the aged right hippocampus or a greater involvement of the left hippocampus in spatial working memory problems. The integrity of the hippocampus is required for normal learning and remembering in a number of tasks (e.g., Cohen & Eichenbaum, 1993; O'Keefe & Nadel, 1978; Redish, 1999; Squire, 1992). One of the primary correlates of hippocampal neuron activity in rats is selective firing as a function of the animal's location in space (O'Keefe & Dostrovsky, 1971). Furthermore, measures of activity from a small, random sample of pyramidal cells (30-150) allow accurate predictions of the rat's location in an environment

The Aging Brain and Neurodegenerative Disorders

Abstract: Both the aging brain and neurodegenerative disorders are characterized by a lack of longevity of affected neurons resulting in their death.1 Neuronal shrinkage or atrophy and death are both normal and inevitable aspects of “successful” aging. This is distinct from the unexpected, excessive, and premature, in neurodegenerative disorders.

Delayed and Blunted Induction of mRNA for Tissue Plasminogen Activator in the Brain of Old Rats Following Pentylenetetrazole-Induced Seizure Activity

Abstract: The ability of the rodent brain to support plasticity-related phenomena declines with increasing age. Here we investigated the extent to which old rats retain the capacity to initiate transcription for immediate early genes, particularly as it relates to brain plasticity, in response to a strong stimulus. The intraperitoneal administration of pentylenetetrazole (PTZ) to rats of various ages evoked tonic-clonic seizures. Using an RNA gel-blot and in situ hybridization analysis, we found that 1 hour after the onset of seizure, messenger RNA (mRNA) for tissue plasminogen activator (TPA) was increased approximately 3.7-fold in the hippocampi of 3-month-old rats. The levels of TPA mRNA in the hippocampi and cortices of 3-month-old rats returned to control levels by 3 hours after PTZ administration. The levels of TPA mRNA increased 2.5-fold in the hippocampi of 18-month-old rats and 1.8-fold in the brains of the 28-month-old-rats at 3 hours and returned to basal levels by 15 hours following PTZ treatment. Quantitatively similar increases were calculated for the cortex. At peak induction the transcripts were localized throughout the cortical layers of the 3-month-old rats, whereas the TPA mRNA expression was restricted to cortical layer V of the older rats. Our results suggest that although the aging brain retains the capacity to respond to chemically induced seizures, the induction of TPA mRNA is temporarily delayed and the levels are diminished with increasing age. Because TPA has been implicated in neuronal plasticity, this finding suggests that immediate early genes are important factors in the limited plasticity of the aging brain.

Methods for modulation of the effects of aging on the primate brain

Abstract: The invention provides a clinically useful protocol for delivery of recombinant nervous system growth factors into the aging mammalian brain. The invention is particularly useful in tempering and reversing the loss of neurological function in the aging mammalian brain, by (a) correlating loss of cortical fiber density to impairment of neurological function in the normal, aging brain; and (b) providing minimally invasive means by which such losses may be reversed. To these ends, a method is provided by which a growth factor-encoding transgene is delivered to, and expressed in, preselected sites within the brain, to stimulate growth of neurons at, and at a distance from, each delivery site.

Neurotechnique Imaging Physiologic Dysfunction of Individual Hippocampal Subregions in Humans and Genetically Modified Mice

Abstract: with genetic lesions. To overcome this limitation, we have developed an approach, applicable to both mice and human subjects, based on nontask-related magnetic resonance imaging that relies on a resting rather than dynamic signal. Scott A. Small,* Ed X. Wu, Dusan Bartsch, Gerard M. Perera, Clay O. Lacefield, Robert DeLaPaz, Richard Mayeux, Yaakov Stern, and Eric R. Kandel The Departments of Neurology and Radiology The current magnetic resonance imaging experiments The Taub Institute for Research on are based on the principle that T2* (magnetic susceptiAlzheimer’s Disease and the Aging Brain bility) is sensitive to the ratio of oxyhemoglobin to deoxyHoward Hughes Medical Institute hemoglobin (Ogawa et al., 1990), which is an indirect Center for Neurobiology and Behavior correlate of neuronal function. Since functional MRI College of Physicians and Surgeons (fMRI) first was developed in the early 1990s, nearly all Columbia University studies have focused on the dynamic shift in T2* signal 630 West 168th Street associated with an activation task, and the success of New York, New York 10032 this analysis has led to the remarkable expansion in the use of fMRI in cognitive neuroscience. Task-induced measurements of dynamic T2* signal introduces several Summary limitations, however. Detecting changes in the T2* signal requires MRI techniques that use rapidly shifting magWe have developed a variant of functional magnetic netic gradients designed to enhance temporal resoluresonance imaging (fMRI) designed to be sensitive tion. The enhanced temporal resolution obtained with to static neuronal function. This method is based on these methods comes at the expense of a reduction in resting instead of dynamic changes in oxygen-depenspatial and anatomical resolution (Frahm et al., 1993). dent signal and therefore allows for a spatial resolution As a result, dynamic fMRI only has a spatial resolution that can detect signal from different hippocampal subof a few millimeters, and this resolution is insufficient regions in human subjects as well as in mice. We found for evaluating many brain structures such as the subrethat hippocampal signal was significantly diminished gions of the hippocampus (Stern and Hasselmo, 1999). in elderly subjects with memory decline compared to In addition to restricted anatomical resolution, other age-matched controls, and different subjects showed limitations are introduced by requiring subjects to perdysfunction in different subregions. Among healthy form an activation task. In certain brain diseases, subelders, signal intensity from the subiculum was corjects cannot perform the required task. In patients with related selectively with memory performance. This Alzheimer’s disease, for example, one can only use an method does not require an activation task; it can be activation task to evaluate patients with mild disease used in anesthetized normal and in genetically modi(Small et al., 1999), since patients with moderate to sefied and cognitively impaired mice. In mice the signal vere dementia cannot understand the experimental inwas found to be sufficiently sensitive to detect funcstructions. Activation tasks are even more limiting in tional changes in the absence of underlying anatomistudies of small animals where anesthesia is needed cal changes. typically to prevent motion-related artifacts. To overcome the limitations imposed by a task-oriIntroduction ented dynamic T2* signal, we have turned to examining nontask-oriented experiments based on resting T2* sigA major advance in cognitive neuroscience has come nal. The idea of using resting T2* signal derived from from the development of structural and functional imthe consideration that most causes of brain dysfunction aging that allows visualization of specific brain regions produce changes not only in the active but also in the in behaving human subjects. Recently, it has become resting function of neurons. Electroencephalography possible to carry out functional imaging experiments (EEG) recordings have shown that the resting firing in nonhuman primates (Logothetis et al., 1999). This patterns of neuronal populations are changed in many research strategy should allow studies in which human neurological diseases and can occur in the absence of and nonhuman primates perform similar behaviors. A structural damage. More recent studies with positron parallel strategy of this sort encourages the analysis of emission tomography (PET) (for example, Eberling et al., imaging experiments to move beyond obtaining correla1997; Small et al., 2000) have extended these observations between a behavior and a signal in a given region tions by showing that changes in resting neuronal meof the human brain to doing intervention experiments in tabolism occurs with relatively subtle changes in brain nonhuman primates that are designed to examine the function. Changes in resting neuronal function are correcausal relationships between a signal in a brain region lated with resting oxyhemoglobin concentrations as and the behavior under study. Still lacking in this repershown in a study where EEG measurements where coutory of imaging methodologies, however, has been a pled with near-infrared spectroscopy (Hoshi et al., 1998). technique that would extend these comparisons to mice Similar studies have shown a disproportionate change in oxyhemoglobin in the setting of brain disease (Fallgatter et al., 1997). Because resting T2* signal is known to * To whom correspondence should be addressed (e-mail: sas68@