Risk factors for dementia: data from the Conselice study of brain aging.

Among the age-related diseases, the development of cognitive impairments, in particular dementia, is the most devastating for the individual and has great social and healthcare costs. Accurate information is needed about the prevalence and incidence of cognitive disorders and the physiology of the aging brain. In particular, only scarce data are available about the relationship between aging, cognitive status and nutritional factors. In order to address these issues, we planned the Conselice Study, a longitudinal study of physiological and pathological brain aging. The center involved in the study was the municipality of Conselice, (Province of Ravenna), in the Northern-Italian Region Emilia-Romagna. A total of 1,016 subjects aged 65 years and over was enrolled at baseline. Information about cognitive status at 4-years of follow-up was collected from 940 of them. These data have been used to estimate prevalence and incidence of dementia in the elderly Italian population and to investigate the possible role of homocysteine as a predictor of dementia.

Effects of carvedilol on left ventricular diastolic function and chamber volumes in advanced heart failure.

AIM: Carvedilol treatment in chronic heart failure (CHF) demonstrated to reduce mortality and rehospitalisation, and improvement of cardiac systolic function with reduction of left ventricular volumes and remodelling. The effects of the drug on left ventricular (LV) filling are less studied. Systolic dysfunction is often associated to diastolic alteration, pseudonormal and restrictive filling pattern are related with poor prognosis. In this study we evaluated diastolic cardiac modifications during carvedilol therapy at early and long term in patients with advanced CHF and pseudonormal or restrictive filling pattern by echo Doppler method. METHODS: We studied 59 patients with severe but stable CHF (40 in class NYHA III and 19 in class NYHA IV) with both systolic and diastolic dysfunction due to idiopathic or ischemic cardiomyopathy. Group I (n=32) received preceding treatment plus carvedilol and Group II (n=27) continued standard therapy with ACE-inhibitors, diuretics, digossin and vasodilators. In all subjects were evaluated LV volumes mass and ejection fraction (EF). Therefore, we studied transmitral filling parameters: Early filling wave (E), atrial filling wave (A), E/A ratio, deceleration time of E (DT) and isovolumetric releasing time (IVRT) by echo Doppler method. RESULTS: After 4 months of therapy carvedilol group showed a significant increase of A wave (p<0.001) DT (p<0.0001) and IVRT (p<0.0001), and significant reduction of E/A ratio (p<0.0005) respect to Group II. Any significant changes were observed for volumes mass and EF. Transmitral Doppler measurements remained unchanged or further ameliorated at 12 months (A p<0.0005; DT p<0.00002; IVRT p<0.000004; E/A p<0.0008), we also observed E wave reduction (p<0.001) in Group I respect to controls. Besides, after 1 year of follow-up we observed a reduction of systolic volume (p<0.001) pulmonary pressure (p<0.0001) and consequent increase of EF (p<0.001) in group treated with beta-blockers. Multivariate analysis demonstrated that Doppler modification were minimally related to heart rate and blood pressure reduction. CONCLUSIONS: Carvedilol treatment improve diastolic function in CHF with severe diastolic impairment driving restrictive or pseudonormal filling pattern towards altered pattern at early time. These changes remained also after 1 year of therapy and appeared to precede increase of systolic function and improvement of emodynamic status.

Long-term ethanol consumption by rats: effect on acetylcholine release in vivo, choline acetyltransferase activity, and behavior.

The extent and duration of cholinergic hypofunction induced by long-term ethanol consumption was investigated in the rat. Ethanol (20% v/v) was administered to male adult Wistar rats as a sole source of fluid for three or six months. Control rats received tap water. The body weight, food and fluid intake in ethanol-treated rats were lower than in control rats throughout the treatment. After three months of ethanol consumption, and one week withdrawal, acetylcholine release in freely moving rats, investigated by microdialysis technique coupled to high-performance liquid chromatography quantification, was significantly decreased by 57 and 32% in the hippocampus and cortex, respectively, while choline acetyltransferase activity was significantly decreased (-30%) only in the hippocampus. A complete recovery of choline acetyltransferase activity and acetylcholine release was found after four ethanol-free weeks. Conversely, after four weeks of withdrawal following six months of ethanol treatment, the recovery in acetylcholine release was not accompanied by that in choline acetyltransferase activity, which remained significantly lower than in control rats in both cortex and hippocampus. The ability of rats to negotiate active and passive avoidance conditioned response tasks, tested after four ethanol-free weeks, was strongly impaired in both three- and six-month ethanol-treated rats. In conclusion, our experiments demonstrate that the development of a long-lasting cholinergic hypofunction requires at least six months of ethanol administration. The hypofunction affects choline acetyltransferase activity and acetylcholine release differently, and undergoes a remarkable recovery.

Differential effects of amyloid peptides beta-(1-40) and beta-(25-35) injections into the rat nucleus basalis.

The nucleus basalis of male Charles River Wistar rats was injected with 10 micrograms of the beta-amyloid peptides beta-(1-40) and beta-(25-35) and changes in the morphology of the lesioned area, the release of acetylcholine from the cortex, and in behavior were investigated. Injections of saline and a scrambled (25-35) peptide were used as controls. One week after lesioning, a Congo Red-positive deposit of aggregated material was found at the beta-peptides injection site, which lasted for about 21 days in the case of the beta-(25-35) peptide and at least two months for beta-(1-40). No deposit was detected after scrambled peptide injection. At one week post injection, an extensive glial reaction surrounded the injection site of all peptides and saline as well. Such a reaction was still present but rather attenuated after two months. A decrease in the number of cholinergic neurons was detected in the nucleus basalis after one week with all treatments except saline. After two months, a reduction in the number of choline acetyltransferase-immunopositive neurons was still detectable in the rats injected with beta-(1-40) but not in the beta-(25-35)-or scrambled-injected. The reduction in choline acetyltransferase immunoreactivity was closely paralleled by a decrease in basal acetylcholine release from the parietal cortex ipsilateral to the lesion. Disruption of object recognition was observed in the first weeks after beta-(25-35) peptide injection, whereas the beta-(1-40) peptide impaired the performance only two months after lesion. Rats with lesions induced by beta-peptides may be a useful animal model of amyloid deposition for investigation of the pathogenetic mechanisms leading to Alzheimer's disease.

The selective cyclooxygenase-2 inhibitor rofecoxib suppresses brain inflammation and protects cholinergic neurons from excitotoxic degeneration in vivo.

Brain inflammatory processes underlie the pathogenesis of Alzheimer's disease, and non-steroidal anti-inflammatory drugs have a protective effect in the disease. The aim of this work was to study in vivo whether attenuation of brain inflammatory response to excitotoxic insult by the selective cyclooxygenase-2 inhibitor, rofecoxib, may prevent neurodegeneration, as a contribution to a better understanding of the role inflammation plays in the pathology of Alzheimer's disease. We investigated, by immunohistochemical methods, glia reaction, the activation of p38 mitogen-activated protein kinase (p38MAPK) pathway with an antibody selective for the phosphorylated form of the enzyme and the number of choline acetyltransferase-positive neurons and, by in vivo microdialysis, cortical extracellular levels of acetylcholine following the injection of quisqualic acid into the right nucleus basalis of adult rats. Seven days after injection, a marked reduction in the number of choline acetyltransferase-positive neurons was found, along with an intense glia reaction, selective activation of p38MAPK at the injection site and a significant decrease in the extracellular levels of acetylcholine in the cortex ipsilateral to the injection site. The loss of cholinergic neurons persisted for at least up to 28 days. Rofecoxib (3 mg/kg/day, starting 1 h prior to injection of quisqualic acid) treatment for 7 days significantly attenuated glia activation and prevented the loss of choline acetyltransferase-positive cells and a decrease in cortical acetylcholine release. The prevention of cholinergic cell loss by rofecoxib occurred concomitantly with the inhibition of p38MAPK phosphorylation. Our findings suggest an important role of brain inflammatory reaction in cholinergic degeneration and demonstrate a neuroprotective effect of rofecoxib, presumably mediated through the inhibition of p38MAPK phosphorylation.

Selective muscarinic antagonists differentially affect in vivo acetylcholine release and memory performances of young and aged rats.

Brain acetylcholine release and memory performance were investigated in young (three- to six-months) and old (20- to 24-months) rats. Acetylcholine release was measured in vivo in the cortex and hippocampus of freely-moving animals, under basal conditions and in the presence of the following muscarinic antagonists: scopolamine, (+/-)-5,11-dihydro-11-[[(2-[2-[(dipropylamino) methyl]-1-piperidinyl]ethyl) amino] carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepine-6-one (AFDX 384) and pirenzepine. The amount of acetylcholine released from the cortex and hippocampus of old rats was significantly reduced. In the presence of scopolamine and AFDX 384 but not of pirenzepine, the acetylcholine release was significantly higher in the old than the young rats, suggesting that changes in presynaptic M2/M4 muscarinic receptor function occur with ageing in the two brain regions. Cognitive capacities were evaluated using two different behavioural tasks: object recognition and passive avoidance response. Old rats were unable to discriminate between familiar and novel objects and had impaired performance in the passive avoidance test. AFDX 384 restored the performance in both tests. Furthermore, in young rats AFDX 384 reversed the impairment of both object recognition and passive avoidance response induced by scopolamine. The effect of AFDX 384 on acetylcholine release and behaviour in the old rats offers further support to a relationship between the age-related cholinergic hypofunction and cognitive impairment and indicates the blockade of presynaptic muscarinic receptors as a possible selective target for therapeutic strategies aimed at improving age-associated memory deficits.

Long-term changes in the aggregation state and toxic effects of beta-amyloid injected into the rat brain.

The long-term effects of beta-amyloid peptide 1-40 injection into the rat forebrain were studied. Ten micrograms of pre-aggregated peptide were injected into the right nucleus basalis of male Wistar rats which were then killed four or six months later. Congo Red staining of histological sections showed that the peptide deposit was aggregated in a fibrillary form four months post-surgery, whereas at six months almost no trace of birefringency was detected at the deposit site, indicating a loss of fibril organization. This result was confirmed by electron microscopic analysis of the peptide deposits. The presence of the peptide at the injection site six months post-surgery was demonstrated by both Haematoxylin staining and beta-amyloid immunoreactivity. The number of choline acetyltransferase-immunoreactive neurons was reduced by 66% in the injected nucleus basalis four months after injection. A decrease in cortical acetylcholine release was also found at this time. Concomitantly with the loss of fibril conformation, a complete recovery of choline acetyltransferase immunoreactivity in the nucleus basalis and of acetylcholine release in the cortex was observed at six months. These data provide in vivo evidence that beta-amyloid neurotoxicity is related to the fibrillary conformation of the peptide aggregates, thus confirming previous in vitro studies.

Rivastigmine antagonizes deficits in prepulse inhibition induced by selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis.

Impairments of cortical cholinergic inputs from the nucleus basalis magnocellularis fundamentally alter information processing and attentional function, thereby advancing the severity of psychopathology in major neuropsychiatric disorders. It was previously shown in adult rats that bilateral 192 IgG saporin-induced selective immunolesioning of the cholinergic neurons in the nucleus basalis produces pronounced and long-lasting deficits in sensorimotor gating measured by prepulse inhibition of the startle reflex. This behavioral paradigm is considered a valid model of sensorimotor gating deficits in the psychotic spectrum and efforts to analyze the significance of the cholinergic basal forebrain in this context are of great interest. In the present study the predictive value of the selective cholinergic immunolesioning model was tested by examining the ability of the cholinesterase inhibitor rivastigmine to restore prepulse inhibition in immunolesioned rats. We report here a pronounced restoring effect of acute (0.75 or 1.5 mg/kg s.c.) as well as repeated (0.75 mg/kg s.c. b.i.d., for 10 days) treatment with rivastigmine in this model of disrupted prepulse inhibition. Intra-nucleus basalis magnocellularis infusions of 192 IgG saporin resulted in extensive loss of basal-cortical cholinergic neurons as shown by the marked decrease in basal telencephalic choline acetyltransferase immunopositive neurons and cortical choline acetyltransferase activity. In this condition, rivastigmine was found to significantly increase cortical acetylcholine extracellular levels in lesioned animals measured by in vivo microdialysis. Taken together, our results strengthen the proposal that the nucleus basalis represents a critical station of the startle gating circuitry. In addition, our findings strongly indicate that even after dramatic decrease of cholinergic neurons, inhibition of acetylcholinesterase restores the cholinergic synaptic function to a point approaching normalization of experimentally induced psychopathology.

Interleukin-1beta activates forebrain glial cells and increases nitric oxide production and cortical glutamate and GABA release in vivo: implications for Alzheimer's disease.

Interleukin-1beta (10 U) was injected into the nucleus basalis of adult male Wistar rats. The inflammation-induced changes in glial cell morphology and expression of inducible nitric oxide synthase in the injected area, the release of acetylcholine, GABA and glutamate from the ipsilateral cortex, the production of nitrite levels in the injected area and ipsilateral cortex, and changes in motor activity were investigated. Saline-injected rats were used as control. Interleukin-1beta induced an activation of both microglia and astrocytes which was already evident 24 h after injection. Seven days after injection, many reactive microglial cells and astrocytes were seen in the injected area and in other brain regions of the same hemisphere. Microglia reaction, but not astrocyte activation, disappeared 30 days post-injection. Seven days after interleukin-1beta injection, many cells immunopositive for inducible nitric oxide synthase were found surrounding the injection site. Inducible nitric oxide synthase-positive cells were identified, by double staining immunohistochemistry, in the reactive microglial cells and, by electron microscope examination, in the perineuronal subpopulation of resident activated microglia. Microdialysis investigations revealed a transient increase in reactive nitrogen intermediates (at seven days post-injection), a delayed (at 30 days post-injection) increase in GABA and glutamate release, and no changes in acetylcholine release in the ipsilateral cortex in interleukin-1beta, but not saline, injected rats. Inhibition of inducible nitric oxide synthase expression by N(G)-nitro-L-arginine methyl ester administration prevented the increase in nitrogen intermediates and GABA release, but not in glutamate release. Our findings suggest that an inflammatory reaction of the basal forebrain facilitates GABA release through the production of nitric oxide.

Effects of novelty, pain and stress on hippocampal extracellular acetylcholine levels in male rats.

In vivo microdialysis was used to assess the effects of Novelty, persistent pain (Formalin test) and stress (Restraint) on hippocampal acetylcholine (ACh) release. Experiments were carried out during the dark phase, i.e. during the active period of the animal, and consisted of four experimental phases: Baseline (30 min), Novelty (30 min), Formalin test (90 min) and Restraint (30 min); each animal was consecutively exposed to all phases. The extracellular levels of ACh in the dorsal hippocampus were estimated by measurement of its concentration in the perfusion fluid by high-performance liquid chromatography with electrochemical detection. The introduction to a new environment (Novelty) induced in all rats higher ACh levels than Baseline. Formalin treatment decreased ACh release only in animals considered 'Inactive' during the Novelty phase while no modification in ACh release was observed in the 'Active' ones. Restraint did not produce any modification of ACh release but increased Corticosterone plasma levels both in sham- and formalin-treated animals. Results indicate that Novelty, but not Formalin or Restraint, increases ACh release in the hippocampus and that the type of behavioral state displayed by the animal at the time of formalin injection determines the response of the septo-hippocampal cholinergic pathway.

Administration of amyloid beta-peptides into the medial septum of rats decreases acetylcholine release from hippocampus in vivo.

The septum of male Wistar rats was injected with synthetic beta-amyloid fragments, beta 12-28, beta 25-35 and beta 1-40, and hippocampal acetylcholine (ACh) release was evaluated by transversal microdialysis. A marked decrease in basal and K(+)-evoked ACh release was found 7 or 21 days after injection of 5 nmol of beta 12-28 and beta 25-35, or 3 nmol of beta 1-40, respectively. These data indicate that septal injection of beta-amyloid peptides causes hypofunction of the septo-hippocampal cholinergic system.

Effects of novelty and pain on behavior and hippocampal extracellular ACh levels in male and female rats.

In vivo microdialysis was used to assess the effects of novelty and pain on hippocampal ACh release in male and female rats. Experiments were carried out during the dark phase and consisted of 2 days of tests: on Day 1, after Baseline 1, animals were exposed to a new cage (Novelty) to which, 30 min later, a plastic cylinder (Object) was introduced. On Day 2, after Baseline 2, the Formalin test (50 microl of formalin 10%, s.c. injected in the dorsal hindpaw) was carried out in the animal's home cage. All behaviors were recorded. The extracellular levels of ACh in the dorsal hippocampus were estimated, in 10-min samples, by assay of ACh in the dialysates by HPLC. On Day 1 the raw values of ACh were higher in females than in males, but no sex difference was present when the percentage of change was considered. In both sexes the Novelty and Object tests induced an increase in ACh levels with respect to Baseline. Higher levels of exploration were present in females than males during the first 10 min of Novelty. On Day 2, ACh release increased in both sexes during the Formalin test. No sex difference in either ACh raw values or the percentages of change were found. Females showed higher levels of licking and lower levels of activity than males. The present study shows that novelty and pain induce similar hippocampal cholinergic activation in male and female rats but different behaviors. The results are discussed in light of the several anatomical and functional sex differences present in the hippocampus.

Beta(1-40) amyloid peptide injection into the nucleus basalis of rats induces microglia reaction and enhances cortical gamma-aminobutyric acid release in vivo.

The nucleus basalis of adult rats was injected with beta(1-40) amyloid peptide. A marked increase in basal and K(+)-evoked GABA release in the ipsilateral cortex and a significant decrease in GAD activity in the injected NB were found 30 days after injection. An intense activation of microglial cells that surrounded and infiltrated the deposit was observed. These data demonstrate that a local injection of beta(1-40) peptide into the NB induces glia activation and affects GABAergic neurons.

Morphological, biochemical and behavioural changes induced by neurotoxic and inflammatory insults to the nucleus basalis.

Interest in the basal forebrain cholinergic system has greatly increased since neuropathological studies in humans provided evidence that this system is severely affected in Alzheimer's disease and other dementing disorders. In laboratory animals, disruption of the nucleus basalis cholinergic neurones has been produced by several neurotoxic insults in order to obtain a model reproducing the behavioural impairment related to the cholinergic deficits. The experiments reported in this review demonstrate that excitotoxic amino acids, beta-amyloid and lipopolysaccharide, injected directly in the nucleus basalis are toxic to the cholinergic neurones in the rat. The excitotoxin lesions of the nucleus basalis, although not selective, are a useful tool for producing experimental animals with cholinergic hypofunction and for investigating drugs able to ameliorate the cholinergic functions. Local injections of amyloid peptides in the rat nucleus basalis produced cholinergic hypofunction and some behavioural impairment. Finally, an intense glia reaction with a limited cholinergic hypofunction and no behavioural impairment was induced by a 4-week infusion of lipopolysaccharide in the nucleus basalis. In conclusion, all three models, in spite of their limitations, offer useful tools for the study of the pathogenetic mechanisms of Alzheimer's disease and for investigating potentially useful drugs.

Phosphatidylserine reverses the age-dependent decrease in cortical acetylcholine release: a microdialysis study.

In vivo basal acetylcholine (ACh) and choline (Ch) output from the parietal cortex of 3- and 19-month-old freely moving rats was measured by microdialysis. A dialysis tubing was inserted transversally through the parietal cortex 24 h before the experiment. ACh and Ch concentrations were determined in the same perfusate samples by HPLC with electrochemical detection. In 19-month-old rats treated with Tris buffer, ACh and Ch outputs were 39 and 16% lower, respectively, than in 3-month-old rats. Phosphatidylserine (PtdSer) administration (15 mg/kg i.p. daily) for 8 days to 19-month-old rats markedly attenuated the decrease in ACh release. The same treatment did not affect ACh and Ch outputs in 3-month-old rats. ACh and Ch outputs in 19-month-old rats administered either phosphatidylcholine (PtdCho) or o-phospho-dl-serine (P-Ser) (15 mg/kg i.p. daily) for 8 days were as low as in 19-month-old rats receiving Tris buffer only. It is possible that chronic PtdSer treatment improve ACh release in aging rats by increasing the availability of Ch for ACh synthesis.

Effect of subchronic treatment with metrifonate and tacrine on brain cholinergic function in aged F344 rats.

The effects of 21-day treatment with the acetylcholinesterase inhibitors metrifonate (80 mg kg(-1) per os (p.o.)) and tacrine (3 mg kg(-1) p.o.), twice daily, on cortical and hippocampal cholinergic systems were investigated in aged rats (24-26 months). Extracellular acetylcholine levels were measured by transversal microdialysis in vivo; choline acetyltransferase and acetylcholinesterase activities were measured ex vivo by means of radiometric methods. Basal cortical and hippocampal extracellular acetylcholine levels, measured 18 h after the last metrifonate treatment, were about 15 and two folds higher, respectively, than in control and tacrine-treated rats. A challenge with metrifonate further increased cortical and hippocampal acetylcholine levels by about three and four times, respectively. Basal extracellular acetylcholine levels, measured 18 h after the last treatment with tacrine were not statistically different from those of the control rats. A challenge with tacrine increased cortical and hippocampal extracellular acetylcholine levels by about four and two times. A 75% inhibition of cholinesterase activity was found 18 h after the last metrifonate administration, while only a 15% inhibition was detectable 18 h after the last tacrine administration. The challenge with metrifonate or tacrine resulted in 90 and 80% cholinesterase inhibition, respectively. These results demonstrate that in aging rats a subchronic treatment with metrifonate results in a long-lasting, cholinesterase inhibition, and a persistent increase in acetylcholine extracellular levels which compensate for the age-associated cholinergic hypofunction. Metrifonate is therefore a potentially useful agent for the cholinergic deficit accompanying Alzheimer's disease.

Effect of metrifonate on extracellular brain acetylcholine and object recognition in aged rats.

The effects of metrifonate were investigated in 4-6- and 22-24-month-old rats. Extracellular acetylcholine levels were measured by transversal microdialysis in vivo. Baseline extracellular acetylcholine levels in the cerebral cortex and hippocampus were 42% and 60% lower, respectively, in old than in young rats. Old rats did not discriminate between familiar and novel objects. In old rats, metrifonate (80 mg/kg p.o.) brought about 85% inhibition of cholinesterase activity in the cortex and hippocampus, a 4-fold increase in extracellular acetylcholine levels in the cortex only, and restored object recognition. In young rats, metrifonate caused 75% cholinesterase inhibition in the cerebral cortex and hippocampus, a 2-fold increase in cortical and hippocampal extracellular acetylcholine levels, and no effect on object recognition. The slight cholinesterase inhibition following metrifonate (30 mg/kg) in aged rats had no effect on cortical acetylcholine levels and object recognition. In conclusion, metrifonate may improve the age-associated cholinergic hypofunction and cognitive impairment.

Nerve growth factor increases extracellular acetylcholine levels in the parietal cortex and hippocampus of aged rats and restores object recognition.

Male Wistar rats (3- and 20-month-old) were perfused i.c.v. with 1.5 micrograms of either nerve growth factor (NGF) or cytochrome C daily for 14 days. At the end of the infusion, the object-recognition test was carried out and extracellular acetylcholine levels (ACh) were measured in the cortex and hippocampus by transversal microdialysis technique. In 20-month-old control rats, the cortical and hippocampal ACh levels were 35 and 45% lower, respectively, than in 3-month-old rats and the ability to discriminate between a familiar and new object was impared. In the old rats treated with NGF, the ACh release as well as the behavioral performance showed no difference from those of young rats. These findings indicate that both ACh levels and memory impairment are improved in aged rats by NGF treatment and suggest that there is a relationship between object recognition and the activity of the forebrain cholinergic system.

Peripherally injected scopolamine differentially modulates acetylcholine release in vivo in the young and aged rats.

The effect of intraperitoneal administration of scopolamine (1 mg/kg) on acetylcholine (ACh) release in vivo in 3- and 24-month-old freely behaving rats was investigated in the cerebral cortex, hippocampus and striatum by means of transverse microdialysis. In the parietal cortex, the increase in ACh release after scopolamine administration was significantly greater in the old than in the young rats, reaching a maximum increase of about 600 and 300% in the old and young animals, respectively. In the hippocampus, scopolamine caused a larger increase in ACh release in the young (+900%) than in the old rats (+600%). In the striatum of aged rats, a 40% increase occurred only at 40 min after scopolamine administration while in the striatum of young animals the increase lasted for at least 2 h, reaching a maximum of about 100%. These findings demonstrate that the modulation of ACh release in vivo is affected in a different manner in the cerebral cortex than in the hippocampus and striatum by aging.

Experimental brain inflammation and neurodegeneration as model of Alzheimer's disease: protective effects of selective COX-2 inhibitors.

Epidemiological studies indicate that long-term treatment with non-steroidal anti-inflammatory drugs reduces the risk of Alzheimer Disease and may delay its onset or slow its progression. Neuroinflammation occurs in vulnerable regions of the Alzheimer's disease (AD) brain where highly insoluble beta-amyloid (Abeta) peptide deposits and neurofibrillary tangles, as well as damaged neurons and neurites, provide stimuli for inflammation. To elucidate the complex role of inflammation in neurodegenerative processes and the efficacy of selective COX-2 inhibitors in AD, we examined whether the attenuation of brain inflammatory reaction by selective COX-2 inhibitors may protect neurons against neurodegeneration. The data reported in this review show that in in vivo models of brain inflammation and neurodegeneration, the administration of selective COX-2 inhibitors prevent not only the inflammatory reaction, but also the cholinergic hypofunction. Our data may help elucidate the epidemiological findings indicating that anti-inflammatory agents, in particular NSAIDs, reduce the risk of developing AD and may slow its progression.