Gary L. Wenk

Inflammation and Alzheimer’s disease

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimers disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

The nucleus basalis magnocellularis cholinergic system: one hundred years of progress.

The nucleus basalis magnocellularis (NBM) contains a population of large cholinergic (Ch) neurons that send their axons to the entire cortical mantle, the olfactory bulbs, and the amygdala. This is the centennial anniversary of the first exact description of this nucleus by Von Kölliker, who named it in honor of its discoverer. This review will focus upon recent attempts to understand the role of the NBM Ch neurons in higher cognitive function by the use of selective lesion analyses and electrophysiological recording techniques. Behavioral deficits associated with NBM lesions produced by injections of excitatory amino acid agonists have been demonstrated in a variety of tasks. Performance decrements produced by these lesions were initially interpreted as being the result of impairments in learning and memory abilities. However, the precise role of the Ch NBM neurons in these performance deficits could not be more thoroughly investigated until it became possible to produce selective and discrete lesions by injection of the immunotoxin, IgG-192 saporin. The results of investigations using this immunotoxin supported a role for NBM Ch neurons in the performance of tasks that require selected attentional abilities rather than learning and memory per se. These lesion analysis studies suggested that the corticopetal NBM Ch system may be involved in the control of shifting attention to potentially relevant, and brief, sensory stimuli that predict a biologically relevant event, such as a food reward. Electrophysiological evidence has implicated NBM Ch cells in the control of attentional processes, as well as a role in the control and maintenance of arousal and sleep states. Electrophysiological studies also suggest that NBM Ch neurons might influence cortical EEG activity in two ways, by its direct excitatory inputs and by an indirect inhibitory projection to the thalamic reticular nucleus. Taken together with the results of histological and anatomical studies of the basal forebrain, NBM Ch cells appear to be ideally located within the basal forebrain for evaluating sensory stimuli for their level of significance, via inputs from the midbrain and limbic system, and also to modulate intrinsic cortical responsiveness appropriately in order to attend to brief, highly salient sensory stimuli.

Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer's disease

Inflammatory processes may play a critical role in the pathogenesis of the degenerative changes and cognitive impairments associated with Alzheimers disease (AD). In the present study, lipopolysaccharide (LPS) from the cell wall of gram-negative bacteria was used to produce chronic, global inflammation within the brain of young rats. Chronic infusion of LPS (0.25 microgram/h) into the 4th ventricle for four weeks produced (1) an increase in the number of glial fibrillary acidic protein-positive activated astrocytes and OX-6-positive reactive microglia distributed throughout the brain, with the greatest increase occurring within the temporal lobe, particularly the hippocampus, (2) an induction in interleukin-1 beta, tumor necrosis factor-alpha and beta-amyloid precursor protein mRNA levels within the basal forebrain region and hippocampus, (3) the degeneration of hippocampal CA3 pyramidal neurons, and (4) a significant impairment in spatial memory as determined by decreased spontaneous alternation behavior on a T-maze.

Memory impairments following basal forebrain lesions.

The functional contribution of the nucleus basalis magnocellularis (NBM) and medial septal area (MSA) to memory was evaluated in 4 behavioral tasks. The tasks were postoperative acquisition of a win-stay spatial discrimination in a T-maze, a win-shift spatial discrimination on a radial arm maze, active avoidance in a shuttle box, and passive avoidance in a shuttle box. Bilateral lesions were made by injecting ibotenic acid (IBO) into the NBM or MSA. Control rats received operations in which no neurotoxin was injected. When compared to controls, rats with lesions in either the NBM or MSA had significantly impaired choice accuracy in the T-maze and radial maze tasks, took significantly fewer trials to reach criterion in the acquisition, but not the retention of an active avoidance task, and significantly more trials to reach criterion in the passive avoidance task. The results show that equivalent behavioral changes are obtained from lesions in the NBM and MSA in tasks that vary in their type of motivation, reinforcement, response-reinforcement contingency, and response. These behavioral changes suggest that the NBM and MSA may both be involved in memory.

ATTENTION AND THE FRONTAL CORTEX AS EXAMINED BY SIMULTANEOUS TEMPORAL PROCESSING

The brain mechanisms involved in attention and memory were examined by testing rats in temporal discriminations designed to emphasize these cognitive processes. Normal rats were able to time each of two stimuli whether they were presented alone or together. Rats with lesions of the frontal cortex (FC) or nucleus basalis magnocellularis (NBM) were able to time each stimulus when it was presented alone, but not when it was presented together with another stimulus. Rather, these rats timed only the intruding stimulus and ignored the other, demonstrating a failure of divided attention. Rats with lesions of the fimbria-fornix (FF) or medial septal area (MSA) performed the divided attention task normally, but failed to remember the duration of a stimulus that had been terminated temporarily earlier in the trial, demonstrating a failure of working memory. These results provide another informative dissociation between the functions of the frontal and hippocampal systems, emphasizing frontal involvement in attention, and hippocampal involvement in working memory.

Individual differences in aging: Behavioral and neurobiological correlates

The goal of this experiment was to determine the correlations among different behavioral and neurobiological measures in aged rats. Aged Sprague-Dawley rats were given a battery of cognitive and sensorimotor tests, followed by electrophysiological assessment of sleep and biochemical measurements of various neurotransmitter systems. The behavioral tests included the following: Activity level in an open field; short-term and long-term memory of a spatial environment as assessed by habituation: spatial navigation, discrimination reversal, and cue learning in the Morris water pool; spatial memory in a T-maze motivated by escape from water; spatial memory and reversal on the Barnes circular platform task; passive avoidance; motor skills. Sleep was assessed by electrographic cortical records. The following neurotransmitter markers were examined: Choline acetyltransferase; the density of nicotinic, benzodiazepine and glutamine receptors in the cortex and caudate nucleus; endogenous levels of norepinephrine, dopamine, and serotonin in the cortex and hippocampus. The duration of bouts of paradoxical sleep was strongly correlated with several cognitive measures and selected serotonergic markers. This finding suggests that changes in sleep patterns and brain biochemistry contribute directly to deficits in learning and memory, or that the same neurobiological defect contributes to age-related impairments in sleep and in learning and memory.

Age-related changes in multiple neurotransmitter systems in the monkey brain

Age-associated changes in cholinergic, monoaminergic and amino acid neurotransmitter systems were analyzed in 14 brain regions of 23 rhesus monkeys that ranged in age from 2 to 37 years. In the frontal pole, the levels of choline acetyltransferase (ChAT) activity, the density of [3H]ketanserin (serotonin type-2) binding sites and endogenous levels of dopamine, homovanillic acid and serotonin, all expressed per milligram of protein, decreased significantly with aging. In precentral motor cortex, ChAT activity decreased; in parietal and occipital cortex, the number of [3H]ketanserin binding sites decreased while the number of Na+-independent [3H]glutamate binding sites increased with age. In the caudate nucleus, endogenous levels of norepinephrine decreased. This descriptive study indicates that the aging monkey may be a very useful model for future investigations of age-associated transmitter abnormalities similar to those that occur in humans.

CHRONIC TREATMENT OF OLD RATS WITH DONEPEZIL OR GALANTAMINE: EFFECTS ON MEMORY, HIPPOCAMPAL PLASTICITY AND NICOTINIC RECEPTORS

The function of the cholinergic system is known to change during normal aging and in pathological conditions such as Alzheimers disease. The present study was designed to assess, within the same group of old animals, the behavioral, electrophysiological and neurochemical effects of chronic treatment with agents that increase the function of the cholinergic system through both muscarinic and nicotinic mechanisms. Doses were determined that produced 60% cholinesterase inhibition by donepezil and galantamine for the old rats. This was chosen to be analogous to therapeutic levels achieved for treatment of human Alzheimers disease patients with these agents. Because of the well-known age-related changes in spatial memory and hippocampal synaptic plasticity, spatial working memory in the radial eight-arm maze and hippocampal long-term potentiation induction and decay, as well as nicotinic receptor density and affinity, were measured in old rats implanted with minipumps that delivered donepezil, galantamine or saline. There was no effect of drug treatment on baseline synaptic transmission or on the threshold or magnitude of long-term potentiation induction. Both drug treatment groups, however, showed significantly extended long-term potentiation decay times at the perforant path-granule cell synapse over the saline control animals, as measured during the week following induction. Both drugs also elevated the number of nicotinic receptors within the hippocampus and neocortex. This is the first demonstration of cholinergic modulation of synaptic plasticity over the time-course of days. Furthermore, the durability of long-term potentiation was significantly, positively correlated with nicotinic receptor binding in the hippocampus. Chronic treatment with donepezil or galantamine had no significant effect on a well-learned spatial working memory task on the radial maze. These data suggest that the therapeutic doses of cholinesterase inhibitors used to treat patients with Alzheimers disease may have effects on neurophysiology and neurochemistry that are close to the threshold for producing detectable behavioral improvements.

Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease: old and new mechanisms of action

Alzheimers disease (AD) is characterized by cerebral deposits of β‐amyloid (Aβ) peptides and neurofibrillary tangles (NFT) which are surrounded by inflammatory cells. Epidemiological studies have shown that prolonged use of non‐steroidal anti‐inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays the onset of the disease. It has been postulated that some NSAIDs target pathological hallmarks of AD by interacting with several pathways, including the inhibition of cyclooxygenases (COX) and activation of the peroxisome proliferator‐activated receptor γ. A variety of experimental studies indicate that a subset of NSAIDs such as ibuprofen, flurbiprofen, indomethacin and sulindac also possess Aβ‐lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. While COX inhibition occurs at low concentrations in vitro (nM‐low μm range), the Aβ‐lowering activity is observed at high concentrations (≤ 50 μm). Nonetheless, studies with flurbiprofen or ibuprofen in AD transgenic mice show that the effects on Aβ levels or deposition are attained at plasma levels similar to those achieved in humans at therapeutic dosage. Still, it remains to be assessed whether adequate concentrations are reached in the brain. This is a crucial aspect that will allow defining the dose‐window and the length of treatment in future clinical trials. Here, we will discuss how the combination of anti‐amyloidogenic and anti‐inflammatory activities of certain NSAIDs may produce a profile potentially relevant to their clinical use as disease‐modifying agents for the treatment of AD.

An hypothesis on the role of glucose in the mechanism of action of cognitive enhancers

This review presents evidence that some cognition enhancing drugs produce their beneficial effects on learning and memory by increasing the availability of glucose for uptake and utilization into the brain. The hypothesis further suggests that many cognition enhancing drugs act through a peripheral mechanism rather than directly on the brain. The general hypothesis is supported by four independent and converging pieces of evidence: 1) Some cognition enhancing drugs may not cross the blood-brain barrier, but can still facilitate memory; 2) Some cognition enhancing drugs are effective only when injected peripherally, but not when injected directly into the brain; 3) Many cognition enhancing drugs are not effective after adrenalectomy; 4) Cognitive function is correlated with glucose regulation in aged animals and humans. These four lines of research have implications for the role of glucose in the action of specific cognitive enhancers.