Reciprocal changes in expression of mRNA for nerve growth factor and its receptors TrkA and LNGFR in brain of aged rats in relation to maze learning deficits

 Quantitative in situ hybridization was used to examine the expression of mRNA for nerve growth factor (NGF) and its receptors, p140Trk (TrkA) and p75LNGFR (LNGFR), in different brain regions of adult (3-month-old) and aged (27-month-old) Wistar rats. The brain regions studied were hippocampus (dentate gyrus, CA3 region), basal forebrain (medial septum, diagonal band) and caudate-putamen. Prior to hybridization histochemistry behaviorally impaired as well as severely impaired animals were selected from a large group of old rats according to their performance in the Morris water maze. The impaired rats showed longer escape latencies and, thus, implicitly impaired performance in the place version of the task, but did not differ from adult controls on the platform crossing measure registered during the spatial probe trial. The severely impaired rats were significantly impaired on both measures, both in comparison with the adult animals and in comparison with the impaired aged rats. Inspection of the hippocampus revealed no age- or performance-related changes in NGF mRNA levels. The overall expression of TrkA mRNA in basal forebrain and caudate was found to be decreased in the impaired (–20%) as well as the severely impaired aged rats (–17%). A significant increase in p75LNGFR mRNA was found in the basal forebrain of the impaired rats in comparison with the severely impaired aged rats (+35%) and adult animals (+33%). These findings show that age-related maze performance deficits are accompanied by a decrease in basal forebrain and striatal TrkA mRNA expression. The increase in basal forebrain LNGFR mRNA levels observed in impaired, but not severely impaired, aged rats may reflect an early manifestation of processes underlying age-related cognitive deficits and may constitute a restorative and/or compensatory mechanism, since these rats displayed fewer deficits in navigation of the maze. Received: 21 February 1996 / Accepted: 15 October 1996     

Age-related changes in rostral basal forebrain cholinergic and GABAergic projection neurons: relationship with spatial impairment

Both cholinergic and GABAergic projections from the rostral basal forebrain contribute to hippocampal function and mnemonic abilities. While dysfunction of cholinergic neurons has been heavily implicated in age-related memory decline, significantly less is known regarding how age-related changes in codistributed GABAergic projection neurons contribute to a decline in hippocampal-dependent spatial learning. In the current study, confocal stereology was used to quantify cholinergic (choline acetyltransferase [ChAT] immunopositive) neurons, GABAergic projection (glutamic decarboxylase 67 [GAD67] immunopositive) neurons, and total (neuronal nuclei [NeuN] immunopositive) neurons in the rostral basal forebrain of young and aged rats that were first characterized on a spatial learning task. ChAT immunopositive neurons were significantly but modestly reduced in aged rats. Although ChAT immunopositive neuron number was strongly correlated with spatial learning abilities among young rats, the reduction of ChAT immunopositive neurons was not associated with impaired spatial learning in aged rats. In contrast, the number of GAD67 immunopositive neurons was robustly and selectively elevated in aged rats that exhibited impaired spatial learning. Interestingly, the total number of rostral basal forebrain neurons was comparable in young and aged rats, regardless of their cognitive status. These data demonstrate differential effects of age on phenotypically distinct rostral basal forebrain projection neurons, and implicate dysregulated cholinergic and GABAergic septohippocampal circuitry in age-related mnemonic decline.     

Neuroinflammation not associated with cholinergic degeneration in aged-impaired brain

Degeneration of the cholinergic neurons in the basal forebrain and elevation of inflammatory markers are well-established hallmarks of Alzheimer's disease; however, the interplay of these processes in normal aging is not extensively studied. Consequently, we conducted a neuroanatomical investigation to quantify cholinergic neurons and activated microglia in the medial septum/vertical diagonal band (MS/VDB) of young (6 months) and aged (28 months) Fisher 344 × Brown Norway F₁ rats. Aged rats in this study were impaired relative to the young animals in spatial learning ability as assessed in the Morris water maze. Stereological analysis revealed no difference between aged and young rats in the total numbers of cholinergic neurons, demonstrating that loss of cholinergic neurons is not a necessary condition to observe impaired spatial learning in aged rats. In this same region, the total number of activated microglia was substantially greater in aged rats relative to young rats. Jointly, these data demonstrate that aging is characterized by an increase in the basal inflammatory state within the MS/VDB, but this inflammation is not associated with cholinergic neuron death.     

Correlation of cognitive performance and morphological changes in neocortical pyramidal neurons in aging

It is well established that the cerebral cortex undergoes extensive remodeling in aging. In this study, we used behaviorally characterized rats to correlate age-related morphological changes with cognitive impairment. For this, young and aged animals were tested in the Morris water maze to evaluate their cognitive performance. Following behavioral characterization, the animals were perfused and a combination of intracellular labeling and immunohistochemistry was applied. Using this approach, we characterized the dendritic morphology of cortical pyramidal neurons as well as the pattern of glutamatergic and GABAergic appositions on their cell bodies and dendrites. We focused on the association region of the parietal cortex (LtPA) and the medial prefrontal cortex (mPFC) for their involvement in the Morris water maze task. We found an age-related atrophy of distal basal dendrites that did not differ between aged cognitively unimpaired (AU) and aged cognitively impaired animals (AI). Dendritic spines and glutamatergic appositions generally decreased from young to AU and from AU to AI rats. On the other hand, GABAergic appositions only showed a trend towards a decrease in AU rats. Collectively, the data show that the ratio of excitatory/inhibitory inputs was only altered in AI animals. When cortical cholinergic varicosities were labeled on alternate sections, we found that AI animals also had a significant reduction of cortical cholinergic boutons compared with AU or young animals. In aged animals, the density of cortical cholinergic varicosities correlated with the excitatory/inhibitory ratio. Our data suggest that both cholinergic atrophy and an imbalance towards inhibition may contribute to the observed age-associated behavioral impairment.     

Age-related sex differences in spatial learning and basal forebrain cholinergic neurons in F344 rats

Basal forebrain cholinergic neurons are important for spatial learning in rodents. Spatial learning ability is reportedly better in males than females, and declines with age. To examine the role of cholinergic function in sex- or age-related differences in spatial learning, we compared the size of basal forebrain cholinergic neurons (BFCN) of young and aged male and female Fischer 344 (F344) rats that had been trained in the Morris water maze. Young male and female rats were equally proficient in finding the platform during training trials, but probe tests revealed that young male rats had better knowledge of the platform's precise location. Impairments in spatial learning were observed in aged rats, and the advantage of males over females was lost. BFCN were significantly larger in young male than young female rats, and were correlated with spatial memory performance for both groups. BFCN were smaller in aged than young males; no change was seen between young and aged females. In the groups of aged rats the correlation between neuron size and spatial memory was lost. The present findings provide further evidence of a role for the basal forebrain cholinergic system in spatial learning, but reveal a complex interaction between sex, age and behavioral performance.     

Amelioration of cholinergic neurons dysfunction in aged rats depends on the continuous supply of NGF

The present study was designed to examine whether NGF-induced improvement in morphology of senile basal forebrain cholinergic neurons persist after discontinuation of NGF treatment. Trophic effect of continuous intraventricular infusion of NGF was tested in the 4- and 28 months old male Wistar rats immediately after cessation of NGF and 3 or 6 weeks after termination of treatment. Immunohistochemical procedure for ChAT, TrkA, and p75(NTR) receptor has been applied to identify cholinergic cells in the basal forebrain structures. Using the quantitative image analyzer, morphometric and densitometric parameters of cholinergic cells were measured. In untreated 28-month-old rats a reduction in the number, size and intensity of staining of cholinergic neurons was observed in all basal forebrain structures. NGF significantly improved morphological parameters of ChAT- and TrkA-positive cells in aged rats. In 28-month-old rats tested within 3 and 6 weeks after discontinuation of infusion a renewed progressive deterioration of cholinergic phenotype of basal forebrain neurons was observed when compared with the NGF-treated immediately tested group. The parallel staining for p75(NTR) revealed normal morphology of the basal forebrain neurons, despite of the age of rats or the NGF treatment. Analysis of Nissl stained sections also showed that 28-month-old rats did not display significant losses of neurons in the basal forebrain when compared with the young animals. These findings demonstrate that senile impairment of cholinergic neurons is induced by a loss of cholinergic phenotype rather than an acute degeneration of cell bodies. NGF may be beneficial in enhancing cholinergic neurochemical parameters, but the protective effects seem to be dependent on the continuous supply of NGF.     

Markers for biogenic amines in the aged rat brain: relationship to decline in spatial learning ability

The major goal of the study was to evaluate the relationship of brain aging to individual differences in functional decline in rats. Forebrain choline-acetyltransferase (ChAT) and monoamines, including their metabolites, were examined in young and aged male Long-Evans rats in relation to their spatial learning ability. Aged rats that were unimpaired on a spatial learning task exhibited few changes in neurochemistry relative to the young group: each change in this subgroup was also evident in the remaining aged animals that were behaviorally impaired. Additional changes in neurochemical measures only found in the behaviorally impaired aged animals included decreased ChAT in the basal forebrain, striatum, and frontal cortex. A cluster analysis using the 15 neurochemical measures that were sensitive to aging yielded groupings of aged animals that differed with respect to their spatial learning ability, but not in their cue learning latencies. In this analysis the activity of ChAT in the basal forebrain and striatum appeared to be the best predictors of spatial learning impairment.     

Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging.

Rats distributed over five different age groups, 3, 12, 18, 24 and 30 months of age, were screened for their spatial learning and memory ability in the Morris water maze, and the degree of place navigational impairments was correlated with morphological changes in the four major forebrain cholinergic cell groups (medial septum, MS; vertical limb of the diagonal band of Broca, VDB; nucleus basalis magnocellularis, NBM; and striatum) using choline acetyltransferase (ChAT) and nerve growth factor receptor (NGFr) histochemistry. Impaired place navigation developed progressively with age, such that 8% of the 12-month-old rats, 45% of the 18-month-old, 53% of the 24-month-old, and over 90% of the 30-month-old rats were behaviorally impaired. Significant reductions in the number of ChAT/NGFr-positive cell bodies, amounting to between 19 and 45%, were observed in all four cell groups, and the remaining cells were reduced in size (6-24% reduction in cross-sectional area in the oldest age groups). Although the morphological changes were less severe and tended to develop later than the behavioral impairments, there was overall a significant correlation between water maze performance and ChAT/NGFr-positive cell counts, and to a lesser degree also cell size in all four cell groups. These changes were also highly correlated with age. The highest correlations were seen in MS, VDB and NBM, which are known to play a role in spatial memory performance in young rats. The results indicate that degenerative and/or atrophic changes in the forebrain cholinergic system and decline in spatial learning ability are parallel processes during aging. Although the magnitude of the morphological changes does not appear to be substantial enough, by itself, to explain the severe spatial learning impairments that develop in the oldest animals, the present data are consistent with the view that impaired function in the forebrain cholinergic system can contribute to age-dependent cognitive decline in rodents.     

Neonatal lesion of forebrain cholinergic neurons: further characterization of behavioral effects and permanency

Intraventricular injections of 192 IgG-saporin in the neonatal rat caused severe loss of basal forebrain cholinergic neurons and ectopic hippocampal ingrowths. These were evident at 24 months of age and thus, were lifelong consequences of the 192 IgG-saporin treatment. When tested as young adults on a novel water-escape radial arm maze, the rats with this lesion were slower to learn the task, committing significantly more working and reference memory errors before they achieved control level of performance. It is unlikely that this was a result of attentional impairment as the lesioned rats performed as vigilantly as controls in a five choice serial reaction time task. When tested in the Morris water maze at 22 months of age, they were slower at learning the hidden platform location. This contrasts with previous studies which have repeatedly shown that they normally acquire this task as young adults. It was concluded that this neonatal cholinergic lesion has modest but discernable effects on problem solving in young adulthood that are consistent with the reported effects of the lesion on cortical pyramidal neurons. The cognitive effects of the lesion may become more severe in aging, perhaps as a result of the added effects of aging on these neurons.     

The length of hippocampal cholinergic fibers is reduced in the aging brain

Cholinergic deficits occur in the aged hippocampus and they are significant in Alzheimer's disease. Using stereological and biochemical approaches, we characterized the cholinergic septohippocampal pathway in old (24 months) and young adult (3 months) rats. The total length of choline acetyltransferase (ChAT)-positive fibers in the dorsal hippocampus was significantly decreased by 32% with aging (F((1,9))=20.94, p=0.0014), along with the levels of synaptophysin, a presynaptic marker. No significant changes were detected in ChAT activity or in the amounts of ChAT protein, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tropomyosin related kinase receptor (Trk) A, TrkB, or p75 neurotrophin receptor (p75(NTR)) in the aged dorsal hippocampus. The number and size of ChAT-positive neurons and the levels of ChAT activity, NGF and BDNF were not statistically different in the septum of aged and young adult rats. This study suggests that substantial synaptic loss and cholinergic axonal degeneration occurs during aging and reinforces the importance of therapies that can protect axons and promote their growth in order to restore cholinergic neurotransmission.     

Deficits across multiple cognitive domains in a subset of aged Fischer 344 rats

Rodent models of cognitive aging routinely use spatial performance on the water maze to characterize medial temporal lobe integrity. Water maze performance is dependent upon this system and, as in the aged human population, individual differences in learning abilities are reliably observed among spatially characterized aged rats. However, unlike human aging in which cognitive deficits rarely occur in isolation, few non-spatial learning deficits have been identified in association with spatial impairment among aged rats. In this study, a subset of male aged Fischer 344 rats was impaired both in water maze and odor discrimination tasks, whereas other aged cohorts performed on par with young adult rats in both settings. The odor discrimination learning deficits were reliable across multiple problems. Moreover, these deficits were not a consequence of anosmia and were specific to olfactory learning, as cognitively impaired aged rats performed normally on an analogous non-olfactory discrimination task. These are among the first data to describe an aging model in which individual variability among aged rat cognition occurs across two independent behavioral domains.     

胰岛素与尼莫地平对大鼠基底前脑胆碱能神经元及空间学习记忆的影响

目的探讨胰岛素与尼莫地平对基底前脑胆碱能神经元与学习记忆在1型糖尿病脑病发生中的影响。方法将成年雄性Wistar大鼠随机分成糖尿病组、干预组、载体组及正常对照组。用链脲佐菌素成功建立成1型糖尿病模型12周后,对干预组大鼠每日皮下注射长效胰岛素(3 IU)、腹腔注射尼莫地平(20 mg/kg),连续用药6周,在相同条件下对载体组大鼠注射等体积的无药物液体,但对糖尿病组或正常对照组大鼠未进行任何处理。应用Morris水迷宫及胆碱乙酰转移酶(ChAT)免疫组化方法,分别测定各组大鼠的空间学习记忆能力及基底前脑胆碱能神经元的变化。结果糖尿病组大鼠内侧隔核、斜角带核垂直支、斜角带核水平支的ChAT阳性神经元数均明显减少(P<0.05),空间学习记忆能力也明显下降(P<0.05);干预组大鼠以上三个核团的ChAT阳性神经元数与学习记忆能力均明显大于糖尿病组大鼠(P<0.05),但干预组的各项指标仍然明显低于载体组大鼠或正常对照组大鼠(P<0.05)。结论在糖尿病的长期自然发展过程中,若不进行治疗则可累及到基底前脑胆碱能神经元,导致学习记忆障碍,这可能是引发1型糖尿病脑病的一个负性因素;此时联合应用胰岛素与尼莫地平仍可有效遏制该脑病向纵深发展的恶性势头。     

Nerve growth factor improves spatial learning and restores hippocampal cholinergic fibers in rats withdrawn from chronic treatment with ethanol

The cholinergic septohippocampal pathway has long been known to be important for learning and memory. Prolonged intake of ethanol causes enduring memory deficits, which are paralleled by partial depletion of hippocampal cholinergic afferents. We hypothesized that exogenous supply of nerve growth factor (NGF), known to serve as a trophic substance for septal cholinergic neurons, can revert the ethanol-induced changes in the septohippocampal cholinergic system. Adult rats were given a 20% ethanol solution as their only source of fluid for 6 months. During the first 4 weeks after the animals were withdrawn from ethanol, they were intraventricularly infused with either NGF or vehicle alone via implanted osmotic minipumps. The vehicle-infused withdrawn animals showed impaired performance on a spatial reference memory version of the Morris water maze task, both during the task acquisition and on the retention test. In contrast, NGF-treated withdrawn rats were able to learn the task as well as controls, and significantly outperformed the vehicle-infused withdrawn rats. The histological analysis revealed that, in the latter group, the length density of fibers immunoreactive to choline acetyltransferase was reduced relative to control values by approximately 25%, as measured in the dentate gyrus and regio superior of the hippocampal formation. However, in NGF-treated withdrawn rats, the length density of these fibers was identical to that of control rats. These data provide support to the notion that NGF is capable of ameliorating memory deficits and restoring septohippocampal cholinergic projections following chronic treatment with ethanol. Electronic Publication     

Age difference of response strategy in radial maze performance of Fischer-344 rats

Age and sex differences in learning performance in an 8-arm radial maze were examined in Fischer-344 rats (aged: 22-27 months; young: 3-4 months). Results of total responses and initial correct responses showed impaired performance in aged rats. There was a sex difference only in initial correct responses of the aged group. In agreement with findings of previous studies, these results demonstrated deficits of spatial learning performance in aged rats. A response strategy was examined as a factor which may affect radial maze performance. Our results revealed that age groups utilized different response strategies to solve the task and appeared similar to reports of maze performance of young animals with experimentally impaired cholinergic function. The results suggest that age difference in a response strategy is due to deterioration of cholinergic system in aged rats, and factors which may have a relationship with the impaired performance in aged rats were discussed, including alteration of response strategy.     

An evaluation of spatial information processing in aged rats

The spatial learning abilities of young, middle-age, and senescent rats were investigated in two experiments using several versions of the Morris water maze task. In Experiment 1, Long-Evans hooded rats were trained to find a submerged escape platform hidden within the water maze. During this phase of testing, aged rats exhibited acquisition deficits compared with either young or middle-age subjects. With continued training, however, all age groups eventually achieved comparable asymptotic levels of performance. Subsequent testing in Experiment 1 revealed that following original training, aged rats were not impaired in learning a novel escape location or in their ability to locate a visible, cued escape platform. In an attempt to identify the basis of the age-related impairments observed in Experiment 1, naive young and aged rats in Experiment 2 were initially tested for their ability to locate a cued escape platform in the water maze. During this phase of testing, the escape latencies of both young and aged rats rapidly decreased to equivalent asymptotic levels. Subsequent analyses revealed that following cue training, young subjects exhibit a significant spatial bias for the region of the testing apparatus where the platform was positioned during training. In contrast, aged rats showed no spatial bias. Training was continued in Experiment 2 using a novel submerged platform location for each subject. During these place training trials, the escape latencies of senescent rats were longer than those of young subjects. These impairments were also accompanied by a lack of spatial bias among aged rats relative to young control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPA- and ibotenic acid-induced excitotoxic lesions of the basal forebrain in rats: differential dependence on cholinergic neuronal loss

Excitotoxic lesions of the basal forebrain were made by infusing either alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or ibotenic acid. Acquisition and performance of spatial learning in the Morris water maze, over a ten day, two trials per day, training regimen were unaffected by the AMPA-induced lesions which reduced cortical choline acetyltransferase activity by 70%. However, acquisition was significantly impaired in rats with ibotenic acid-induced lesions that reduced cortical choline acetyltransferase by 50%. Additionally, ibotenic acid-lesioned rats swam further than either sham or AMPA-lesioned rats, in the "training" quadrant during a probe trial, in which the escape platform was removed, suggesting a perseverative search strategy. Lesions induced with AMPA, but not ibotenate, significantly impaired the acquisition of "step-through" passive avoidance. Both AMPA- and ibotenate-induced lesions significantly impaired the 96 h retention of passive avoidance, but the effect of AMPA was greater on latency measures. Histological analysis revealed that AMPA infusions destroyed more choline acetyltransferase-immunoreactive neurons than did ibotenate infusions but, unlike ibotenate, spared the overlying dorsal pallidum and also parvocellular, non-choline acetyltransferase-immunoreactive neurons in the ventral pallidal/substantia innominata region of the basal forebrain. The impairment in acquisition of the water maze following ibotenate-induced basal forebrain lesions therefore appears unrelated to damage to cholinergic neurons of the nucleus basalis of Meynert and to depend instead on damage to pallidal and other neurons in this area. The AMPA- and perhaps also the ibotenate-induced impairment in the retention of passive avoidance appears to be more directly related to destruction of cholinergic neurons of the nucleus basalis. These data are discussed in the context of cortical cholinergic involvement in mnemonic processes.     

Neuronal and inducible nitric oxide synthase expressions and activities in the hippocampi and cortices of young adult,aged cognitively unimpaired,and impaired Long-Evans rats

Nitric oxide (NO) is a neurosignaling molecule that appears to play a significant role in learning and memory. This molecule has also been implicated in neurotoxicity due to its oxidative properties. Previous experiments from our laboratories have demonstrated elevated hippocampal and cortical neuronal nitric oxide synthase (NOS) mRNA levels in aged cognitively unimpaired and impaired Long-Evans rats, which could represent either increased neuronal NOS activity thereby leading to NO-mediated neurotoxicity, or a compensatory response by aged neurones to maintain physiological nitric oxide output. The current study measured the protein expression and activity levels of neuronal and inducible NOS in young adult (6 months) and aged (24-26 months) Long-Evans rats by means of western blotting and NOS activity assay. Aged animals were assigned as either cognitively unimpaired or aged with moderate cognitive impairments based on their performances in the Morris water maze behavioural task. Our results showed that hippocampal and cortical neuronal NOS expressions were significantly decreased in aged animals. These aged animals also exhibited increased hippocampal and cortical inducible NOS expressions. Between the two aged animal groups, cognitively impaired rats showed significantly lower hippocampal and cortical neuronal but higher hippocampal inducible NOS expressions. Young adult rats exhibited significantly higher hippocampal and cortical NOS activities than the aged animals. Aged animals with cognitive deficits showed significantly lower hippocampal NOS activity than cognitively unimpaired aged rats.Our data indicate that aging is associated with a decline in neuronal but elevated inducible NOS functioning in brain areas involved in learning and memory. These phenomena could contribute to the cognitive deficits observed in a sub-population of aged animals.     

Cortical peroxynitration of nerve growth factor in aged and cognitively impaired rats

Basal forebrain cholinergic neurons (BFCN), a system involved in learning and memory processes, are highly dependent on a continuous supply of biologically active nerve growth factor (NGF). Age-related cholinergic atrophy and cell loss in normal brains is apparently not complemented by reductions in the levels of NGF as could be expected. In the present work, cortical proNGF/NGF were immunoprecipitated from cortical brain homogenates from young and aged and behaviorally characterized rats and resolved with antinitrotyrosine antibodies to reveal nitration of tyrosine residues in proteins. Cortical proNGF in aged and cognitively impaired rats was found to be a target for peroxynitrite-mediated oxidative damage with correlative impact on decrease in choline acetyltransferase activity. These studies provide evidence for oxidative stress damage of NGF molecules in the cerebral cortex of cognitively impaired aged rats as previously shown in AD human brains.     

Imbalance towards inhibition as a substrate of aging-associated cognitive impairment

The number of synapses in the cerebral cortex decreases with aging. However, how this structural change translates into the cognitive impairment observed in aged animals remains unknown. Aged animals are not a homogenous group with respect to their cognitive performances; but instead, they can be separated into aged cognitively unimpaired ("normal") and aged cognitively impaired groups using a spatial memory task such as the Morris water maze. These two aged groups provide an unprecedented opportunity to isolate synaptic properties that relate to cognitive impairment from unrelated factors associated with normal aging. Using such classification, we conducted whole-cell patch-clamp recordings to measure basal spontaneous miniature excitatory (mEPSCs) and inhibitory synaptic currents (mIPSCs) bombarding layer V pyramidal neurons in the parietal cortex. We found that the frequencies of both mEPSC and mIPSC were lower in aged normal rats when compared with young rats. In contrast, aged cognitively impaired rats displayed a reduction in mEPSC frequency only. This results in an imbalance towards inhibition that may be an important substrate of the cognitive impairment in aged animals. We also found that pyramidal neurons in both aged normal and aged cognitively impaired rats exhibit similar structural attritions. Thus, cognitive impairment may be more related to an altered balance between different neurotransmitter systems than a mere reduction in synaptic structures.     

Evaluation of cholinergic markers in Alzheimer's disease and in a model of cholinergic deficit

Cognitive deficits in neuropsychiatric disorders, such as Alzheimer's disease (AD), have been closely related to cholinergic deficits. We have compared different markers of cholinergic function to assess the best biomarker of cognitive deficits associated to cholinergic hypoactivity. In post-mortem frontal cortex from AD patients, acetylcholine (ACh) levels, cholinacetyltransferase (ChAT) and acetylcholinesterase (AChE) activity were all reduced compared to controls. Both ChAT and AChE activity showed a significant correlation with cognitive deficits. In the frontal cortex of rats with a selective cholinergic lesion, all cholinergic parameters measured (ACh levels, ChAT and AChE activities, "in vitro" and "in vivo" basal ACh release) were significantly reduced. AChE activity was associated to ChAT activity, and even more, to "in vivo" and "in vitro" basal ACh release. Quantification of AChE activity is performed by an easy and cheap method and therefore, these results suggest that determination of AChE activity may be used as an effective first step method to evaluate cholinergic deficits.