Aβ-infused Rats Research Articles

Geraniol improves passive avoidance memory and hippocampal synaptic plasticity deficits in a rat model of Alzheimer's disease

Alzheimer's disease (AD) is the most progressive and irreversible neurodegenerative disease that leads to synaptic loss and cognitive decline. The present study was designed to evaluate the effects of geraniol (GR), a valuable acyclic monoterpene alcohol, with protective and therapeutic effects, on passive avoidance memory, hippocampal synaptic plasticity, and amyloid-beta (Aβ) plaques formation in an AD rat model induced by intracerebroventricular (ICV) microinjection of Aβ1-40. Seventy male Wistar rats were randomly into sham, control, control-GR (100 mg/kg; P.O. (orally), AD, GR-AD (100 mg/kg; P.O.; pretreatment), AD-GR (100 mg/kg; P.O.; treatment), and GR-AD-GR (100 mg/kg; P.O.; pretreatment & treatment). Administration of GR was continued for four consecutive weeks. Training for the passive avoidance test was carried out on the 36th day and a memory retention test was performed 24 h later. On day 38, hippocampal synaptic plasticity (long-term potentiation; LTP) was recorded in perforant path-dentate gyrus (PP-DG) synapses to assess field excitatory postsynaptic potentials (fEPSPs) slope and population spike (PS) amplitude. Subsequently, Aβ plaques were identified in the hippocampus by Congo red staining. The results showed that Aβ microinjection increased passive avoidance memory impairment, suppressed of hippocampal LTP induction, and enhanced of Aβ plaque formation in the hippocampus. Interestingly, oral administration of GR improved passive avoidance memory deficit, ameliorated hippocampal LTP impairment, and reduced Aβ plaque accumulation in the Aβ-infused rats. The results suggest that GR mitigates Aβ-induced passive avoidance memory impairment, possibly through alleviation of hippocampal synaptic dysfunction and inhibition of Aβ plaque formation.

Policosanol protects against Alzheimer's disease-associated spatial cognitive decline in male rats: possible involved mechanisms.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline and synaptic failure. The present study was designed to explore the possible protective effects of policosanol (PCO) on spatial cognitive capacity, long-term potentiation (LTP) induction, oxidant/antioxidant status, and Aβ plaques formation in an AD rat model induced by intracerebroventricular (ICV) injection of Aβ1-40. Healthy adult male Wistar rats were randomly divided into control, sham (ICV injection of 5µl phosphate-buffered saline), AG (50mg/kg; P.O., as PCO vehicle), PCO (50mg/kg; P.O.), AD model (ICV injection of 5µl Aβ), AD + AG (50mg/kg; P.O.), and AD + PCO (50mg/kg; P.O.). Treatments were performed for eight consecutive weeks. At the end of the treatment course, spatial learning and memory functions, hippocampal long-term potentiation (LTP) induction, malondialdehyde (MDA), and total thiol group (TTG) levels, as well as the formation of Aβ plaques, were examined. The results showed that injection of Aβ reduced spatial learning and memory abilities in the Barnes maze test, which was accompanied by decreases in field excitatory postsynaptic potential (fEPSP) slope, population spike (PS) amplitude, and TTG level and increases in Aβ plaque accumulation and MDA content. In contrast, PCO treatment improved all the above-mentioned changes in the Aβ-infused rats. The results suggest that amelioration of hippocampal synaptic plasticity impairment, modulation of oxidant/antioxidant status, and inhibition of Aβ plaque formation by PCO may be the mechanisms behind its protective effect against AD-associated spatial cognitive decline.

Looking for a Treatment for the Early Stage of Alzheimer's Disease: Preclinical Evidence with Co-Ultramicronized Palmitoylethanolamide and Luteolin.

Background: At the earliest stage of Alzheimer’s disease (AD), although patients are still asymptomatic, cerebral alterations have already been triggered. In addition to beta amyloid (Aβ) accumulation, both glial alterations and neuroinflammation have been documented at this stage. Starting treatment at this prodromal AD stage could be a valuable therapeutic strategy. AD requires long-term care; therefore, only compounds with a high safety profile can be used, such as the new formulation containing palmitoylethanolamide and luteolin (co-ultra PEALut) already approved for human use. Therefore, we investigated it in an in vivo pharmacological study that focused on the prodromal stage of AD. Methods: We tested the anti-inflammatory and neuroprotective effects of co-ultra PEALut (5 mg/Kg) administered for 14 days in rats that received once, 5 µg Aβ(1–42) into the hippocampus. Results: Glial activation and elevated levels of proinflammatory mediators were observed in Aβ-infused rats. Early administration of co-ultra PEALut prevented the Aβ-induced astrogliosis and microgliosis, the upregulation in gene expression of pro-inflammatory cytokines and enzymes, as well as the reduction of mRNA levels BDNF and GDNF. Our findings also highlight an important neuroprotective effect of co-ultra PEALut treatment, which promoted neuronal survival. Conclusions: Our results reveal the presence of cellular and molecular modifications in the prodromal stage of AD. Moreover, the data presented here demonstrate the ability of co-ultra PEALut to normalize such Aβ-induced alterations, suggesting it as a valuable therapeutic strategy.

Rostral intralaminar thalamic deep brain stimulation ameliorates memory deficits and dendritic regression in β-amyloid-infused rats.

Rostral intralaminar thalamic deep brain stimulation (ILN-DBS) has been shown to enhance attention and cognition through neuronal activation and brain plasticity. We examined whether rostral ILN-DBS can also attenuate memory deficits and impaired synaptic plasticity and protect glutamatergic transmission in the rat intraventricular β-amyloid (Aβ) infusion model of Alzheimer's disease (AD). Spatial memory was tested in the Morris water maze (MWM), while structural synaptic plasticity and glutamatergic transmission strength were estimated by measuring dendritic spine densities in dye-injected neurons and tissue expression levels of postsynaptic density protein 95 (PSD-95) in medial prefrontal cortex (mPFC) and hippocampus. All these assessments were compared among the naïve control rats, AD rats, and AD rats with ILN-DBS. We found that a single rostral ILN-DBS treatment significantly improved MWM performance and reversed PSD-95 expression reductions in the mPFC and hippocampal region of Aβ-infused rats. In addition, ILN-DBS preserved dendritic spine densities on mPFC and hippocampal pyramidal neurons. In fact, MWM performance, PSD-95 expression levels, and dendritic spine densities did not differ between naïve control and rostral ILN-DBS treatment groups, indicating near complete amelioration of Aβ-induced spatial memory impairments and dendritic regression. These findings suggest that the ILN is critical for modulating glutamatergic transmission, neural plasticity, and spatial memory functions through widespread effects on distributed brain regions. Further, these findings provide a rationale for examining the therapeutic efficacy of ILN-DBS in AD patients.

Oral Administration of Ethanolamine Glycerophospholipid Containing a High Level of Plasmalogen Improves Memory Impairment in Amyloid β‐Infused Rats

Ethanolamine plasmalogen (PlsEtn), a major phospholipid in neuronal membranes [60-90mol% of ethanolamine glycerophospholipid (EtnGpl)], is specifically decreased in brains from patients with Alzheimer's disease (AD). The present study investigated how PlsEtn administration affects cognitive deficits and lipid composition in an animal model of AD. AD model rats were infused with amyloid-β (Aβ) into the cerebral ventricle and divided into three groups. Control, Egg, and Ascidian groups were then orally administered vehicle, egg yolk EtnGpl (260μmol as EtnGpl/kg BW/day; 10μmol as PlsEtn/kg BW/day), or ascidian viscera EtnGpl (260μmol as EtnGpl/kg BW/day; 209μmol as PlsEtn/kg BW/day), respectively. After 4weeks of dosing, Aβ-infused rats were tested for learning ability in an 8-arm radial maze. The administration of ascidian viscera EtnGpl improved both reference and working memory-related learning abilities. In lipid analysis, the Ascidian group showed higher levels of PlsEtn species in the plasma, erythrocytes, and liver when compared to other groups. In addition, although there were no differences at levels of total plasmalogen including choline plasmalogen, the Ascidian group had significantly higher levels of 18:0ol/22:6-PlsEtn in the cerebral cortex. These levels of 18:0ol/22:6-PlsEtn in the cerebral cortex were correlated with working memory-related learning ability. Moreover, 18:0ol/22:6-PlsEtn levels in the cerebral cortex showed positive correlations with those in the erythrocytes and liver. In summary, dietary PlsEtn, especially that with 22:6n-3 (docosahexaenoic acid, DHA), may ameliorate learning deficiencies in AD by altering lipid composition in the brain.

Schisandrin B Ameliorates ICV-Infused Amyloid β Induced Oxidative Stress and Neuronal Dysfunction through Inhibiting RAGE/NF-κB/MAPK and Up-Regulating HSP/Beclin Expression.

Amyloid β (Aβ)-induced neurotoxicity is a major pathological mechanism of Alzheimer’s disease (AD). Our previous studies have demonstrated that schisandrin B (Sch B), an antioxidant lignan from Schisandra chinensis, could protect mouse brain against scopolamine- and cisplatin-induced neuronal dysfunction. In the present study, we examined the protective effect of Sch B against intracerebroventricular (ICV)-infused Aβ-induced neuronal dysfunction in rat cortex and explored the potential mechanism of its action. Our results showed that 26 days co-administration of Sch B significantly improved the behavioral performance of Aβ (1–40)-infused rats in step-through test. At the same time, Sch B attenuated Aβ-induced increases in oxidative and nitrosative stresses, inflammatory markers such as inducible nitric oxide syntheses, cyclooxygenase-2, interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, and DNA damage. Several proteins such as receptor for advanced glycation end products (RAGE), nuclear factor-κB, mitogen-activated protein kinases, and apoptosis markers were over expressed in Aβ-infused rats but were significantly inhibited by Sch B treatment. Furthermore, Sch B negatively modulated the Aβ level with simultaneous up-regulation of HSP70 and beclin, autophagy markers in Aβ-infused rats. The aforementioned effects of Sch B suggest its protective role against Aβ-induced neurotoxicity through intervention in the negative cycle of RAGE-mediated Aβ accumulation during AD patho-physiology.

Changes in insulin-signaling transduction pathway underlie learning/memory deficits in an Alzheimer’s disease rat model

Brain metabolic dysregulation is a hallmark pathological change in Alzheimer's disease (AD). Although detailed mechanisms are still not fully elucidated, recent studies suggest alterations of insulin-signaling transduction cascades underlie neuronal stresses in AD brains. In this study, we performed in vivo experiments to determine the impact of soluble Aβ oligomers on insulin-signaling transduction in rat hippocampi by utilizing lateral ventricular injection of amyloid beta (Aβ) oligomers on male Wistar rats (225±25g, 3-4months old) as an AD rat model. The Aβ-infused rats manifested remarkably increased escape latency and significantly decreased proportions of time and pathway crossing the hidden platform as compared to the rats in the pseudo-injection group and the non-injection group in Morris water maze test implicating the damaging effect of soluble Aβ oligomers on rat learning and memory functions. Accordingly, our subsequent results demonstrated that the infusion of soluble Aβ oligomers significantly decreased the expressions of insulin receptor, insulin receptor substrate-I, B cell lymphoma/leukemia-2 and serine/threonine protein kinase B in rat hippocampal neurons, whereas the expression level of total cAMP response element-binding protein was not changed. This study suggests that soluble Aβ oligomers instigated insulin-signaling disturbances which are potentially associated with learning and memory deficits in the AD rat model.

Ibuprofen-Glutathione Conjugate as Anti-inflammatory and Anti-apoptotic Agent in Rat Brain Infused with β Amyloid (1-40)

Background: To date it is proved that Alzheimer’s disease (AD) is characterized by a multifactorial etiology which comprises mitochondrial dysfunction, energy depletion, inflammation, and oxidative stress associated with glutathione depletion. All these factors are known to be impacted by beta amyloid protein (Aβ), which is responsible for the activation of amyloidogenic cascade. In the present work a rat intracerebroventricular Aβ(1-40) infusion model of early AD was employed to investigate the effects of Ibuprofen-Glutathione (IBU-GSH) conjugate on morphological modifications, Aβ plaque formation, apoptosis, learning, and memory performance. Methods: Water maze test was used to evaluate drug administration effects on spatial reference memory, immunohistochemistry was carried out to determine Aβ 1-40, iNOS and caspase-3 expression; semithin sections and ultrastructural analyses, by means of light and transmission electron microscopy, respectively, were realized to evaluate samples morphology; TUNEL analysis to identify apoptotic cells. Results and Conclusion: Results showed that in the Aβ+IBU-GSH conjugate treated group, long-term memory consolidation at day 12 was improved, while learning appeared slower respect to control. In Aβ-infused rats, a higher number of Aβ plaques, disorganized pyramidal pyknotic cells, apoptotic cells containing fragmented or swollen mitochondria, dilated blood vessels, and a low number of oligodendrocytes along with the high expression of inducible Nitric Oxide Synthase (iNOS) and caspase-3 were put in evidence. The inflammatory state seemed to be reversed by IBU-GSH treatment, as evidenced by a lower number of Aβ plaques and pyknotic cells, and reorganized neurons containing normal mitochondria; despite this, persistent dilated blood vessels, decreased iNOS expression, lower percentage of apoptosis, and weak caspase-3 levels were observed. Thus mitochondria involvement in the AD inflammatory state is here strongly suggested and neuro-protective and anti-apoptotic IBU-GSH conjugate effect could be useful to reduce the AD inflammatory state.

Elevation of BACE in an Aβ rat model of Alzheimer's disease: exacerbation by chronic stress and prevention by nicotine

In Alzheimer's disease (AD), progressive accumulation of β-amyloid (Aβ) peptides impairs nicotinic acetylcholine receptor (nAChR) function by a mechanism that may involve α7 and α4β2-nAChR subtypes. Additionally, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), the rate-limiting enzyme in the pathogenic Aβ production pathway, is expressed at high levels in hippocampal and cortical regions of AD brains. We measured hippocampal area CA1 protein levels of BACE and α7- and α4β2-nAChR subunits using an Aβ rat model of AD (14-d osmotic pump i.c.v. infusion of 300 pmol/d Aβ peptides) in the presence and absence of chronic stress and/or chronic nicotine treatment. There was a significant increase in the levels of BACE in Aβ-infused rats, which were markedly intensified by chronic (4-6 wk) stress, but were normalized in Aβ rats chronically treated with nicotine (1 mg/kg b.i.d.). The levels of the three subunits α7, α4 and β2 were significantly decreased in Aβ rats, but these were also normalized in Aβ rats chronically treated with nicotine. Chronic stress did not further aggravate the reduction of nAChRs in Aβ-infused rats. The increased BACE levels and decreased nAChR levels, which are established hallmarks of AD, provide additional support for the validity of the Aβ i.c.v.-infused rat as a model of AD.

Protective effects of prescription n-3 fatty acids against impairment of spatial cognitive learning ability in amyloid β-infused rats

Deposition of amyloid β peptide (Aβ) into the brain causes cognitive impairment. We investigated whether prescription pre-administration of n-3 fatty acids improves cognitive learning ability in young rats and whether it protects against learning ability impairments in an animal model of Alzheimer's disease that was prepared by infusion of Aβ(1-40) into the cerebral ventricles of rats. Pre-administration of TAK-085 (highly purified and concentrated n-3 fatty acids containing eicosapentaenoic acid ethyl ester and docosahexaenoic acid ethyl ester) at 300 mg kg(-1) day(-1) for 12 weeks significantly reduced the number of reference memory errors in an 8-arm radial maze, suggesting that long-term administration of TAK-085 improves cognitive leaning ability in rats. After pre-administration, the control group was divided into the vehicle and Aβ-infused groups, whereas the TAK-085 pre-administration group was divided into the TAK-085 and TAK-085 + Aβ groups (TAK-085-pre-administered Aβ-infused rats). Aβ(1-40) or vehicle was infused into the cerebral ventricle using a mini osmotic pump. Pre-administration of TAK-085 to the Aβ-infused rats significantly suppressed the number of reference and working memory errors and decreased the levels of lipid peroxide and reactive oxygen species in the cerebral cortex and hippocampus of Aβ-infused rats, suggesting that TAK-085 increases antioxidative defenses. The present study suggests that long-term administration of TAK-085 is a possible therapeutic agent for protecting against Alzheimer's disease-induced learning deficiencies.

The protective effect of dietary eicosapentaenoic acid against impairment of spatial cognition learning ability in rats infused with amyloid β (1–40)

Background Amyloid β (Aβ) peptide (1–40) can cause cognitive impairment. Experimental design We investigated whether dietary preadministration of eicosapentaenoic acid (EPA) is conducive to cognition learning ability and whether it protects against the impairment of learning ability in rats infused with Aβ peptide (1–40) into the cerebral ventricle. Results Dietary EPA administered to rats for 12 weeks before the infusion of Aβ into the rat brain significantly decreased the number of reference memory errors (RMEs) and working memory errors (WMEs), suggesting that chronic administration of EPA improves cognition learning ability in rats. EPA preadministered to the Aβ-infused rats significantly reduced the increase in the number of RMEs and WMEs, with concurrent proportional increases in the levels of corticohippocampal EPA and docosahexaenoic acid (DHA) and in the DHA/arachidonic acid molar ratio. Decrease in oxidative stress in these tissues was evaluated by determining the reactive oxygen species and lipid peroxide levels. cDNA microarray analysis revealed that altered genes included those that control synaptic signal transduction, cell communication, membrane-related vesicular transport functions, and enzymes and several other proteins. Conclusion The present study suggests that EPA, by acting as a precursor for DHA, ameliorates learning deficits associated with Alzheimer's disease and that these effects are modulated by the expression of proteins involved in neuronal plasticity.

Green tea catechins prevent cognitive deficits caused by Aβ 1–40 in rats

Amyloid β peptide (Aβ)-induced oxidative stress is involved in the pathogenesis of Alzheimer's disease (AD). In contrast, green tea catechins confer potent antioxidative defense to brain neurons. Therefore, we examined whether long-term administration of green tea catechins [Polyphenon E (PE): 63% of epigallocatechin-3-gallate, 11% of epicatechin, 6% of (−)-epigallocatechin and 6% of (−)-epicatechin-gallate] prevents cognitive impairment in an animal model of AD, rats infused with Aβ 1–40 into the cerebral ventricle. Five-week-old male Wistar rats fed with an MF diet were randomly divided into two groups: 0.0% PE (rats administered with water only) and 0.5% PE (rats administered with 5 g/L of PE). Twenty weeks after the PE administration, the 0.0% PE group was divided into the Vehicle group (rats infused with the solvent used for dissolving Aβ) and the Aβ 1–40-infused rat group (Aβ group), whereas the 0.5% PE group was divided into the PE+Vehicle group (PE-preadministered vehicle-infused rats) and the PE+Aβ group (PE-preadministered Aβ-infused rats). Aβ 1–40 or vehicle was infused into the cerebral ventricle using a mini osmotic pump. Behavioral changes in the rats were assessed by an eight-arm radial maze. PE administration for 26 weeks significantly decreased the Aβ-induced increase in the number of reference and working memory errors, with a concomitant reduction of hippocampal lipid peroxide (LPO; 40%) and cortico-hippocampal reactive oxygen species (ROS; 42% and 50%, respectively). Significantly reduced levels of LPO in the plasma (24%) and hippocampus (25%) as well as those of ROS in the hippocampus (23%) and cortex (41%) were found in the PE+Vehicle group as compared with the Vehicle group. Furthermore, rats with preadministered PE had higher ferric-reducing antioxidation power of plasma as compared with the Vehicle group. Our results suggest that long-term administration of green tea catechins provides effective prophylactic benefits against Aβ-induced cognitive impairment by increasing antioxidative defenses.

β-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or β-amyloid deposits

beta-Amyloid (Abeta) polypeptide plays a critical role in the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of Abeta deposits and neurofibrillary tangles, and loss of neurons. Increased genetic production or direct intracerebral administration of Abeta in animal models results in Abeta deposition, gliosis, and impaired cognitive functions. Whether aging renders the brain prone to Abeta and whether inflammation is required for Abeta-induced learning deficits is unclear. We show that intraventricular infusion of Abeta1-42 results in learning deficits in 9-month-old but not 2.5-month-old mice. Deficits that become detectable 12 weeks after the infusion are associated with a slight reduction in Cu,Zn superoxide dismutase activity but do not correlate with Abeta deposition and are not associated with gliosis. In rats, Abeta infusion induced learning deficits that were detectable 6 months after the infusion. Approximately 20% of the Abeta immunoreactivity in rats was associated with astrocytes. NMR spectrum analysis of the animals cerebrospinal fluid revealed a strong reduction trend in several metabolites in Abeta-infused rats, including lactate and myo-inositol, supporting the idea of dysfunctional astrocytes. Even a subtle increase in brain Abeta1-42 concentration may disrupt normal metabolism of astrocytes, resulting in altered neuronal functions and age-related development of learning deficits independent of Abeta deposition and inflammation.

α7 Nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal LTP induction in β-amyloid infused rats

Continuous intracerebroventricular infusion of β-amyloid peptide 1–40 (Aβ (1–40)) in animal models induces learning and memory impairment associated with dysfunction of the cholinergic neuronal system, which has been considered to be a pathological model of Alzheimer's disease [Nitta, A., Itoh, A., Hasegawa, T., Nabeshima, T., 1994. β-amyloid protein-induced Alzheimer's disease animal model. Neurosci. Lett. 170, 63–66.]. Here, using a real-time optical recording technique, we demonstrate that basal synaptic transmission and several forms of synaptic plasticity, including long-term potentiation (LTP), post-tetanic potentiation (PTP) and paired-pulse facilitation (PPF) are deficient at the Schaffer collateral–CA1 synapse in hippocampal slices from Aβ-infused brain. Throughout this study, an effort was made to address whether the α7 nicotinic acetylcholine receptor (α7nAChR), which is believed to be a primary target of Aβ [Wang, H.Y., Lee, D.H., Davis, C.B., Shank, R.P., 2000a. Amyloid peptide Aβ (1–42) binds selectively and with picomolar affinity to alpha 7 nicotinic acetylcholine receptors. J. Neurochem. 75, 1155–1161.], is responsible for the deficits in synaptic plasticity observed in the Aβ-infused rats. First, we found that Aβ-infusion markedly depressed the response of α7nAChR to a selective α7nAChR agonist [3-(2,4-dimethoxybenzylidene)-anabaseine] (DMXB). Second, blockade of α7nAChR with either methyllycaconitine (MLA) or α-bungarotoxin (α-BTX) in control rats inhibited LTP induction, suggesting that the activation of α7nAChR is required for LTP induction. Finally, pre-treatment of the slices from Aβ-infused rats with 10 μM DMXB rescued CA1 synapses from the deficit in LTP and PPF. These results suggest that Aβ-impaired LTP and PPF arise as a consequence of dysfunctional α7nAChR, and that α7nAChR may be an important target to help ameliorate AD patient cognitive deficits.

Estrogen (E2) and glucocorticoid (Gc) effects on microglia and Aβ clearance in vitro and in vivo

The accumulation of fibrillar aggregates of beta Amyloid (Aβ) in Alzheimer's Disease (AD) brain is associated with chronic brain inflammation. Although activated microglia (μglia) can potentially clear toxic amyloid, chronic activation may lead to excessive production of neurotoxins. Recent epidemiological and clinical data have raised questions about the use of anti-inflammatory steroids (glucocorticoids, Gcs) and estrogens for treatment or prevention of AD. Since very little is known about steroid effects on μglial interactions with amyloid, we investigated the effects of the synthetic Gc dexamethasone (DXM) and 17-β estradiol (E2) in vitro in a murine μglial-like N9 cell line on toxin production and intracellular Aβ accumulation. To determine whether the steroid alterations of Aβ uptake in vitro had relevance in vivo, we examined the effects of these steroids on Aβ accumulation and μglial responses to Aβ infused into rat brain. Our in vitro data demonstrate for the first time that Gc dose-dependently enhanced μglial Aβ accumulation and support previous work showing that E2 enhances Aβ uptake. Despite both steroids enhancing uptake, degradation was impeded, particularly with Gcs. Distinct differences between the two steroids were observed in their effect on toxin production and cell viability. Gc dose-dependently increased toxicity and potentiated Aβ induction of nitric oxide, while E2 promoted cell viability and inhibited Aβ induction of nitric oxide. The steroid enhancement of μglial uptake and impedence of degradation observed in vitro were consistent with observations from in vivo studies. In the brains of Aβ-infused rats, the μglial staining in entorhinal cortex layer 3, not associated with Aβ deposits was increased in response to Aβ infusion and this effect was blocked by feeding rats prednisolone. In contrast, E2 enhanced μglial staining in Aβ-infused rats. Aβ-immunoreactive (ir) deposits were quantitatively smaller, appeared denser, and were associated with robust μglial responses. Despite the fact that steroid produced a smaller more focal deposit, total extracted Aβ in cortical homogenate was elevated. Together, the in vivo and in vitro data support a role for steroids in plaque compaction. Our data are also consistent with the hypothesis that although E2 is less potent than Gc in impeding Aβ degradation, long term exposure to both steroids could reduce Aβ clearance and clinical utility. These data showing Gc potentiation of Aβ-induced μglial toxins may help explain the lack of epidemiological correlation for AD. The failure of both steroids to accelerate Aβ degradation may explain their lack of efficacy for treatment of AD.