Stephen W. Scheff

Evidence of increased oxidative damage in subjects with mild cognitive impairment

Objective: To determine if increased levels of oxidative damage are present in the brains of persons with mild cognitive impairment (MCI), a condition that often precedes Alzheimer disease (AD). Methods: The authors assessed the amount of protein carbonyls, thiobarbituric acid-reactive substances (TBARS), and malondialdehyde in the superior and middle temporal gyri (SMTG) and cerebellum of short postmortem interval and longitudinally evaluated normal subjects and those with MCI and early AD. Results: Elevated levels of protein carbonyls (∼25%), malondialdehyde (∼60%), and TBARS (∼210%) were observed in the SMTG of individuals with MCI and early AD vs normal control subjects. The elevation in TBARS was associated with the numbers of neuritic but not diffuse plaques. Levels of protein carbonyls increased as delayed verbal memory performance declined. Conclusion: Oxidative damage occurs in the brain of subjects with mild cognitive impairment, suggesting that oxidative damage may be one of the earliest events in the onset and progression of Alzheimer disease.

Glutamate as a CNS transmitter. I. Evaluation of glucose and glutamine as precursors for the synthesis of preferentially released glutamate

Slices of the molecular layer of the dentate gyrus of the hippocampal formation were incubated with either [14C]glucose, [14C]pyruvate or 14C glutamine and the efflux of endogenous and radioactive glutamate was monitored under various conditions. After prelabeling with either [14C]glutamine or [14C]glucose elevation of K+ concentration to 56 mM (Ca2+ free) increased efflux of endogenous and [14C]glutamate. Introduction of Ca2+ into the elevated K+ medium further increased the efflux of endogenous glutamate and radioactive glutamate derived from any of the precursors tested. In glutamine containing media, the increase in glutamate efflux as well as basal efflux was considerably higher than in the absence of glutamine and the specific activity of glutamate release was higher than that in tissue. Thus glutamine was superior to glucose or pyruvate as precursor and most specifically labeled the putative transmitter pool of glutamate. Similar experiments were carried out 4 and 14 days after a unilateral lesion in the entorhinal cortex which provides about 60% of the total synaptic input to the dentate granule cells. The Ca2+ dependent release of glutamate derived from either glucose or glutamine was markedly reduced on the operated side. This result suggests that the transmitter pool of glutamate is in perforant path terminals and can be synthesized from glucose or glutamine.

Elevated corticosterone levels. A possible cause of reduced axon sprouting in aged animals.

Measurements of serum corticosterone taken at three times in the diurnal cycle (08.00, 18.00, and 23.30 h) showed that aged male Sprague-Dawley rats have higher nonstressed circulating levels at two time points measured. To determine if such elevated levels of steroids were sufficient to interfere with lesion-induced sprouting, the corticosterone peak at 18.00 h of either aged or young adult animals was maintained in young adrenalectomized rats by use of subcutaneous corticosterone pellets. The normal young adult animal levels resulted in mild suppression of the adrenergic sprouting response seen in hippocampus following transection of the fimbria-fornix. Young animals maintained at the elevated corticosterone levels of normal senescent rats had marked suppression of sprouting. The levels of circulating glucocorticoids reached by aged rats are sufficient to retard sprouting, and may therefore interfere with synaptic turnover and the response of the senescent brain to damage.

Compensatory synapse growth in aged animals after neuronal death

The capacity of neurons to grow new synapses following partial denervation has been studied in the brain of aged rats and compared to that of younger animals. Lesion induced synapse formation is reduced in aged rats in the hippocampus and septum, two brain areas which show particularly robust growth responses in younger animals. The rate of growth as well as the final magnitude of the response is diminished in aged animals. A possible mechanism for the decreased growth response in aged animals is discussed in light of current models of reactive synaptogenesis. The loss of a compensatory growth response in the aged animal may be one of the factors which contribute to decreased brain plasticity and the slower and poorer recovery from brain damage following injury.

Gonadal steroids influence axon sprouting in the hippocampal dentate gyrus: A sexually dimorphic response

Young adult Sprague-Dawley rats of either sex were randomly assigned to be gonadectomized or left intact. Capsules containing either testosterone or estrogen were implanted in animals in both categories. Fifteen days after removal of the entorhinal cortex, the brains were analyzed for changes in reactive outgrowth of the commissural-associational afferent fibers in the hippocampal dentate gyrus. Both male and female control subjects showed identical sprouting responses. Only female subjects were significantly affected by gonadectomy, resulting in significant decreases in reactive fiber outgrowth. Hormone replacement therapy resulted in a return to control values in castrated females but had no affect on castrated males. The results suggest that sex hormones may regulate axon sprouting in the mature central nervous system.

Volumetric atrophy of the amygdala in Alzheimer's disease: Quantitative serial reconstruction

The present study quantitatively assessed volumes of the amygdala and its subnuclei in autopsied cases of advanced Alzheimers disease (AD) for comparison with age-matched controls. Amygdalar nuclei showed significant atrophy in AD with the exception of the paralaminar portion of the basal nucleus. The magnocellular regions of the amygdala showed proportionately greater size reductions as a fraction of total amygdala volume than did other areas. Computerized reconstruction of the amygdala provided three-dimensional views of a variety of structural alterations accompanying the volumetric declines with AD. The apparent selective vulnerability of the magnocellular amygdalar areas coincides with the loss of large nerve cells in AD.

A new type of lesion-induced synaptogenesis: I. Synaptic turnover in non-denervated zones of the dentate gyrus in young adult rats

It is well established that partial denervation causes the formation of new synapses within denervated areas. It is also possible that synapse formation and remodeling occurs outside denervated zones. In this study we evaluate this possibility by examining the effect of a unilateral entorhinal lesion on the number and characteristics of synapses in non-denervated zones of the dentate gyrus within the hippocampal formation. A unilateral entorhinal lesion massively denervates the outer two-thirds of the ipsilateral dentate molecular layer and also causes a minor loss of synapses in the outer two-thirds of the contralateral dentate molecular layer. The inner one-third of the molecular layer is not denervated on either side. In the ipsilateral inner molecular layer the number of synapses rapidly decreases by about 20% and recovers by 10 days post-lesion. Similarly, in the contralateral inner molecular layer, synapses are lost and replaced, but the time course is slower. Loss is maximal at 60 days post-lesion and this recovers by 180 days post-lesion. Thus, a complete cycle of turnover occurs in both of the inner molecular layers. No degenerating terminals of any type were seen throughout the time course in these layers. Small synapses with non-complex synaptic junctions appear to account for most of the changes. Also the outer two-thirds of the contralateral molecular layer, which has lost less than 5% of its input, loses about 37% of its synapses and replaces the majority of them over time. However, the total number of synapses in the contralateral molecular layer never fully attains the value of unoperated animals. The total synaptic population reaches a value such that the ipsilateral and contralateral molecular layers are nearly equivalent. These changes, achieved through synaptic turnover, may represent a homeostatic response to nearby denervation which may facilitate restoration of bilateral function in the dentate gyrus.

Hydrocortisone administration retards axon sprouting in the rat dentate gyrus

Abstract Glucocorticoids were administered to rats after lesions of the entorhinal cortex and axon sprouting and astrocyte reactivity were assessed in the hippocampus. Glucocorticoids caused a decrease in axon sprouting and elicited hypertrophy of astrocytes.

Recovery of spontaneous alternation following lesions of the entorhinal cortex in adult rats: possible correlation to axon sprouting.

Adult rats with unilateral or bilateral lesions of the entorhinal cortex were tested over time for changes in spontaneous alternation behavior. Rats with bilateral lesions did not display spontaneous alternation throughout the duration of the study. This suggests that the entorhinal area plays an important role in the manifestation of spontaneous alternation. In contrast to rats with bilateral lesions, those with unilateral lesions displayed recovery to preoperative levels of alternation within 10 days after surgery. It is suggested that the circuitry changes accompanying axon sprouting after unilateral lesions may participate in the recovery of spontaneous alternation.

Laminar organization of cholinergic circuits in human frontal cortex in Alzheimer's disease and aging

Cholinergic enzyme activity (choline acetyltransferase, CAT acetylcholinesterase, AChE) and muscarinic cholinergic receptor density were measured in frontal cortex (Brodmanns area 9) of normal patients over the life span and in brains of patients with Alzbeimers disease (AD). CAT, but not AChE activity, declined with normal aging. Significant loss of CAT and AChE activity occurred in the AD brains, but later onset AD was associated with less severe loss of frontal cortex CAT activity. The majority of normal CAT activity resided in lamina I, II, and upper lamina III; CAT loss in AD resulted in large losses from all depths, most notably the upper cortical layers. AChE did not precisely correspond to the localization of CAT; loss of AChE in AD was consistent across all six laminae. No differences were seen in muscarinic cholinergic receptor binding between AD and age-matched controls; the distribution of binding was equal in all layers of normal frontal cortex, and no laminar differences were detected in distribution of cholinergic receptors between normal and AD samples.