Cognitive Impairment In Mouse Model Research Articles

Neurotrophic Factors Mediated Activation of Astrocytes Ameliorate Memory Loss by Amyloid Clearance after Transplantation of Lineage Negative Stem Cells.

Alzheimer's disease (AD) is one of the untreatable neurodegenerative disorders with associated societal burden. Current therapies only provide symptomatic relief without altering the rate of disease progression as reported by Lanctot et al. (Therapeutic Advances in Neurological Disorders 2 (3):163-180, 2009). The increased number of failed clinical trials in last two decades indicates the imperative need to explore alternative therapies for AD as reported by Tuszynski et al. (Nature Medicine 11 (5):551-555, 2005) and Liyanage et al. (Alzheimer's & Dementia 4:628-635, 2005). In this study, we aimed to decipher the role of neurotrophic factors in the reversal of memory loss by transplantation of lineage negative (Lin-ve) stem cells in a male mouse model of cognitive impairment induced by intrahippocampal injection of amyloid β-42 (Aβ-42). The efficacy of human umbilical cord blood (hUCB) derived Lin-ve stem cells were analyzed by neurobehavioral parameters, i.e., Morris water maze and passive avoidance after bilateral intra-hippocampal transplantation using stereotaxic surgery. Real-time PCR and immunohistochemistry was carried out in brain tissues in order to analyze the expression of neurotrophic factors, apoptotic, astrocytic, and other neuronal cell markers. The transplantation of Lin-ve stem cells led to reversal of memory loss associated with reduction of Aβ-42 deposition from the brains. The molecular analysis revealed increase in neurotrophic factors, i.e., glial derived neurotrophic factor (GDNF), ciliary derived neurotrophic factor (CNTF), and Brain-derived neurotrophic factor (BDNF) after transplantation. The administration of ANA-12, a TrkB inhibitor, reversed the behavioral and molecular effects of stem cell transplantation suggesting involvement of BDNF-TrkB pathway in the rescue of memory loss. We believe that the amyloid clearance results from activation of astrocytes and anti-apoptotic pathways added by neurotrophic factors.

Resolving and Rescuing Developmental Miswiring in a Mouse Model of Cognitive Impairment

Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal networks. This dysfunction emerges already during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Here we address this open question combining in vivo electrophysiology, optogenetics, neuroanatomy and behavioral assays during development in mice mimicking the dual genetic – environmental etiology of psychiatric disorders. We report that pyramidal neurons in layer II/III of the prefrontal cortex are key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing relate to sparser dendritic arborization and lower spine density. Transient administration of minocycline, potentially acting via microglial cells, rescues morphological, synaptic and functional neuronal deficits, and restores pre-juvenile cognitive abilities. Elucidation of the cellular substrate of developmental miswiring related to later cognitive deficits opens new perspectives for identification of neurobiological targets, amenable to therapies.

Inhibition of Phosphodiesterase-4 Reverses Aβ-Induced Memory Impairment by Regulation of HPA Axis Related cAMP Signaling.

Beta amyloid peptides (Aβ) are found to be associated with dysfunction of hypothalamic-pituitary-adrenal axis (HPA axis) that leads to memory and cognitive deficits in patients with Alzheimer's disease (AD). Phosphodiesterase 4 (PDE4) inhibitors increase the intracellular cAMP activities, which may ameliorate cognitive deficits associated with AD. However, it remains unclear whether PDE4-mediated reversal of cognitive impairment in mouse model of AD is related to HPA axis and downstream cAMP-dependent pathway. The present study investigated the effects of PDE4 inhibitor rolipram on Aβ1-42-induced cognitive dysfunction and its underlying mechanisms. The step-down passive avoidance (PA) and Morris water-maze (MWM) tests were conducted 1 week (1 W), 2 months (2 M), and 6 months (6 M) after intracerebroventricular microjection (i.c.v.) of Aβ1-42. The results suggested that memory impairment emerged as early as 1 W, peaked at 2 M, and lasted until 6 M after injection. Chronic treatment with rolipram (0.1, 0.5, 1.0 mg/kg/d, i.p.) for 2 weeks (i.e., treatment started at 1.5 months after Aβ1-42 microinjection) dose-dependently improved memory performance in both MWM and PA tests. Moreover, rolipram reversed the Aβ-induced increases in serum corticosterone (CORT), corticotropin-releasing factor, and glucocorticoid receptors (CRF-R and GR) levels, whereas it decreases in brain-derived neurotropic factor (BDNF) and the ratio of pCREB to CREB expression. These effects of rolipram were prevented by pre-treatment with PKA inhibitor H89. The findings indicated that the protective effects of rolipram against Aβ1-42-induced memory deficits might involve HPA axis and cAMP-CREB-BDNF signaling.

Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension.

Hypertension is a leading risk factor for dementia, but the mechanisms underlying its damaging effects on the brain are poorly understood. Due to a lack of energy reserves, the brain relies on continuous delivery of blood flow to its active regions in accordance with their dynamic metabolic needs. Hypertension disrupts these vital regulatory mechanisms, leading to the neuronal dysfunction and damage underlying cognitive impairment. Elucidating the cellular bases of these impairments is essential for developing new therapies. Perivascular macrophages (PVMs) represent a distinct population of resident brain macrophages that serves key homeostatic roles but also has the potential to generate large amounts of reactive oxygen species (ROS). Here, we report that PVMs are critical in driving the alterations in neurovascular regulation and attendant cognitive impairment in mouse models of hypertension. This effect was mediated by an increase in blood-brain barrier permeability that allowed angiotensin II to enter the perivascular space and activate angiotensin type 1 receptors in PVMs, leading to production of ROS through the superoxide-producing enzyme NOX2. These findings unveil a pathogenic role of PVMs in the neurovascular and cognitive dysfunction associated with hypertension and identify these cells as a putative therapeutic target for diseases associated with cerebrovascular oxidative stress.

Effects of varenicline on alpha4-containing nicotinic acetylcholine receptor expression and cognitive performance in mice

Nicotinic acetylcholine receptor (nAChR) subtypes containing the α4 subunit, particularly α4β2 nAChRs, play an important role in cognitive functioning. The impact of the smoking cessation aid varenicline, a selective partial α4β2 nAChR agonist, on (1) changes of central protein and mRNA expression of this receptor and (2) on memory deficits in a mouse model of cognitive impairment was investigated.Protein and mRNA expression of both the α4 and β2 receptor subunits in mouse brain endothelial and hippocampal cells as well as hippocampus and neocortex tissues were determined by western blot and realtime PCR, respectively. The β2 antibody showed low specificity, though. Tissues were examined following a 2-week oral treatment with various doses of varenicline (0.01, 0.1, 1, 3 mg/kg/day) or vehicle. In addition, episodic memory of mice was assessed following this treatment with an object recognition task using (1) normal mice and (2) animals with anticholinergic-induced memory impairment (i.p. injection of 0.5 mg/kg scopolamine).Varenicline dose-dependently increased protein expression of both the α4 and β2 subunit in cell cultures and brain tissues, respectively, but had no effect on mRNA expression of both subunits. Scopolamine injection induced a significant reduction of object memory in vehicle-treated mice. By contrast, cognitive performance was not altered by scopolamine in varenicline-treated mice.In conclusion, a 2-week oral treatment with varenicline prevented memory impairment in the scopolamine mouse model. In parallel, protein, but not mRNA expression was upregulated, suggesting a posttranscriptional mechanism. Our findings suggest a beneficial effect of varenicline on cognitive dysfunction.

Regulatory role of microRNA-30b and plasminogen activator inhibitor-1 in the pathogenesis of cognitive impairment

The present study aimed to investigate the role of plasminogen activator inhibitor-1 (PAI-1) in drug-induced early cognitive impairment and the underlying mechanism concerning microRNA (miR)-30b. A mouse model of cognitive impairment was established by intraperitoneal injection of scopolamine (2 mg/kg body weight) for 13 days. Behavioral performance was assessed using the Morris water maze (MWM) test. The mRNA expression levels of PAI-1 and miR-30b were detected using quantitative polymerase chain reaction (qPCR). The protein expression levels of PAI-1 in the hippocampus and blood were determined using western blot analysis and enzyme-linked immunosorbent assays. The MWM test demonstrated that, on days 3 and 4, the escape latency was significantly elevated in the model mice in comparison with control group (P<0.05). In addition, the length of swimming path was significantly increased (P<0.05), while the number of times of crossing the platform location was significantly reduced in the model mouse group (P<0.05) in comparison with the control group. qPCR demonstrated that the mRNA expression levels of PAI-1 in the model mice was significantly elevated in the hippocampus and blood in comparison with the control group (P<0.01). Furthermore, western blot analysis and enzyme-linked immunosorbent assay demonstrated that the protein expression levels of PAI-1 were significantly elevated in the hippocampus and blood in the model group, in comparison with the control group (P<0.05). Notably, the levels of miR-30b in the hippocampus and blood were significantly decreased in the model mice in comparison with the control group (P<0.01). To conclude, the expression levels of PAI-1 were significantly elevated in mice with scopolamine-induced cognitive impairment, which may be associated with the downregulation of miR-30b. The findings from the present study suggest that miR-30b may be involved in the regulation of PAI-1, which would contribute to the pathogenesis of cognitive impairment.

P3‐042: Altered zinc neuromodulation induces neuronal hyperactivity and cognitive impairment

Altered zinc homeostasis is implicated in the pathology of Alzheimer's disease (AD) through observations that Aβ oligomers (AβO) bind and sequester synaptic zinc, leading to synaptic deficits, and that drugs targeting zinc decrease amyloid beta (Aβ) load and improve cognition in transgenic mouse models of AD. Recently we found age-dependent increases in markers of seizure activity in the hippocampus of a transgenic mouse lacking synaptic zinc (ZnT3KO) that displays age-dependent cognitive deficits. These finding led to our hypothesis that seizure activity resulting from lack of zinc neuromodulation may contribute to development of impaired cognition. We investigated whether levetiracetam, an antiseizure drug in wide clinical use that has been shown to improve cognition in amnestic MCI patients and prevents cognitive impairment in mouse models of AD, would prevent cognitive impairment in ZnT3KO. To determine if suppression of seizure activity during a memory task can rescue the impaired cognition seen in 6 month-old ZnT3KO, we used an acute treatment administering levetiracetam 3.5 hr before training and testing in a hippocampal-dependent object location memory task (OLM). We also tested a chronic 70-day course of treatment by delivering levetiracetam using implanted osmotic pumps before assessing performance of ZnT3KO in the OLM task at 6 months of age. While 6 month ZnT3KO performed slightly above chance levels in the OLM task after acute treatment with levetiracetam, their performance was not significantly improved compared to untreated ZnT3KO mice. Conversely, chronic treatment with levetiracetam markedly improved cognition, with 6 month ZnT3KO performing equivalent to age-matched wild type mice in the OLM task. Prevention of cognitive impairment by chronic treatment with an anti-seizure drug suggests that seizure activity in ZnT3KO mice contributes to neurodegeneration and to cognitive impairment. Though acute treatment to suppress seizure activity during a memory task did not rescue cognition in 6 month ZnT3KO, the slight improvement in performance suggests that treatment at 3 months, when cognition begins to decline, may improve cognition. These results support further investigation of therapies directed to restore zinc homeostasis and normalize excitatory neurotransmission to manage neuronal hyperactivity and associated neurodegenerative changes in AD.

Effect of human umbilical cord blood derived lineage negative stem cells transplanted in amyloid-β induced cognitive impaired mice

Alzheimer's disease (AD) is pathologically characterized by extracellular deposition of insoluble amyloid-β (Aβ) plaques and intracellular tangles made up of phosphorylated tau in brain. Several therapeutic approaches are being carried out in animal AD models for testing their safety and efficacy in altering disease pathology and behavioral deficits. Very few studies have examined the effect of human umbilical cord blood (hUCB) derived stem cells in degenerative disease models despite growing number of cord blood banks worldwide. Here we have examined the therapeutic efficacy of hUCB derived lineage negative (Lin −ve) stem cells in alleviating behavioral and neuropathological deficits in a mouse model of cognitive impairment induced by bilateral intrahippocampal injection of Aβ-42. Lin −ve cells were transplanted at two doses (50,000 and 100,000) at the site of injury and examined at 10 and 60 days post transplantation for rescue of memory deficits. These cells were found to ameliorate cognitive impairment in 50,000—60 days and 100,000—10 days groups whereas, 50,000—10 days and 100,000—60 days groups could not exert any significant improvement. Further, mice showing spatial memory improvement were mediated by up-regulation of BDNF, CREB and also by concomitant down regulation of Fas-L in their brain. The transplanted cells were found in the host tissue and survived up to 60 days without expressing markers of neuronal differentiation or reducing Aβ burden in mouse brain. We suggest that these undifferentiated cells could exert neuroprotective effects either through inhibiting apoptosis and/or trophic effects in the brain.

Sigma-2 receptor binding is decreased in female, but not male, APP/PS1 mice

The sigma-2 receptor is a steroid-binding membrane-associated receptor which has been implicated in cell survival. Sigma-2 has recently been shown to bind amyloid-β (Aβ) oligomers in Alzheimer's disease (AD) brain. Furthermore, blocking this interaction was shown to prevent or reverse the effects of Aβ to cause cognitive impairment in mouse models and synaptic loss in neuronal cultures. In the present work, the density of sigma-2 receptors was measured in a double transgenic mouse model of amyloid-β deposition (APP/PS1). Comparisons were made between males and females and between transgenic and wt animals.Sigma-2 receptor density was assessed by quantitative autoradiography performed on coronal brain slices using [3H]N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl]-2-methoxy-5-methyl-benzamide ([3H]RHM-1), which has a 300-fold selectivity for the sigma-2 receptor over the sigma-1 receptor. The translocator protein of 18 kDa (TSPO) is expressed on activated microglia and is a marker for neuroinflammation. TSPO has been found to be upregulated in neurodegenerative disorders, including AD. Therefore, in parallel with the sigma-2 autoradiography experiments, we measured TSPO expression using the selective radioligand, [3H]PBR28. We also quantified Aβ plaque burden in the same animals using a monoclonal antibody raised against aggregated Aβ.Sigma-2 receptor density was significantly decreased in piriform and motor cortices as well as striata of 16-month old female, but not male, APP/PS1 mice as compared to their wt counterparts. [3H]PBR28 binding and immunostaining for Aβ plaques were significantly increased in piriform and motor cortices of both male and female transgenic mice. In striatum however, significant increases were observed only in females.

Aβ degradation or cerebral perfusion? Divergent effects of multifunctional enzymes.

There is increasing evidence that deficient clearance of β-amyloid (Aβ) contributes to its accumulation in late-onset Alzheimer disease (AD). Several Aβ-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), and angiotensin-converting enzyme (ACE) reduce Aβ levels and protect against cognitive impairment in mouse models of AD. In post-mortem human brain tissue we have found that the activity of these Aβ-degrading enzymes rise with age and increases still further in AD, perhaps as a physiological response that helps to minimize the build-up of Aβ. ECE-1/-2 and ACE are also rate-limiting enzymes in the production of endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictors, increases in the levels of which are likely to contribute to reduced blood flow in AD. This review considers the possible interdependence between Aβ-degrading enzymes, ischemia and Aβ in AD: ischemia has been shown to increase Aβ production both in vitro and in vivo, whereas increased Aβ probably enhances ischemia by vasoconstriction, mediated at least in part by increased ECE and ACE activity. In contrast, NEP activity may help to maintain cerebral perfusion, by reducing the accumulation of Aβ in cerebral blood vessels and lessening its toxicity to vascular smooth muscle cells. In assessing the role of Aβ-degrading proteases in the pathogenesis of AD and, particularly, their potential as therapeutic agents, it is important to bear in mind the multifunctional nature of these enzymes and to consider their effects on other substrates and pathways.

Donepezil and the alpha-7 agonist PHA 568487, but not risperidone, ameliorate spatial memory deficits in a subchronic MK-801 mouse model of cognitive impairment in schizophrenia

Cognitive impairment associated with schizophrenia (CIAS) is an important etiological feature of this disorder with implications for symptom severity and quality of life. Acute N-methyl-d-aspartate receptor (NMDAR) blockade using MK-801, a non-competitive antagonist to NMDARs, is assumed to produce temporary cognitive impairments in mice similar to those seen in schizophrenia patients. Less is known, however, about the effects of subchronic MK-801 administration on cognition. In the current study, twenty-eight male C57/BL6 mice received a daily dose of MK-801 (0.1mg/kg, i.p.) for seven days. Spatial memory was assessed using an object location task prior to MK-801 administration as well as at multiple time points after the treatment. Subchronic treatment with MK-801 caused lasting memory deficits, which were ameliorated by acute doses of an acetylcholinesterase inhibitor (donepezil) and an alpha-7 nicotinic agonist (PHA 568487), but were unaffected by acute administration of the atypical antipsychotic risperidone. Subchronic administration of MK-801 may lend this pharmaceutical model increased face validity, while its resemblance to prodromal schizophrenia makes it suitable for screening new CIAS treatments.

Women with the Alzheimer's risk marker ApoE4 lose Aβ-specific CD4⁺ T cells 10-20 years before men.

Adaptive immunity to self-antigens causes autoimmune disorders, such as multiple sclerosis, psoriasis and type 1 diabetes; paradoxically, T- and B-cell responses to amyloid-β (Aβ) reduce Alzheimer's disease (AD)-associated pathology and cognitive impairment in mouse models of the disease. The manipulation of adaptive immunity has been a promising therapeutic approach for the treatment of AD, although vaccine and anti-Aβ antibody approaches have proven difficult in patients, thus far. CD4+ T cells have a central role in regulating adaptive immune responses to antigens, and Aβ-specific CD4+ T cells have been shown to reduce AD pathology in mouse models. As these cells may facilitate endogenous mechanisms that counter AD, an evaluation of their abundance before and during AD could provide important insights. Aβ-CD4see is a new assay developed to quantify Aβ-specific CD4+ T cells in human blood, using dendritic cells derived from human pluripotent stem cells. In tests of >50 human subjects Aβ-CD4see showed an age-dependent decline of Aβ-specific CD4+ T cells, which occurs earlier in women than men. In aggregate, men showed a 50% decline in these cells by the age of 70 years, but women reached the same level before the age of 60 years. Notably, women who carried the AD risk marker apolipoproteinE-ɛ4 (ApoE4) showed the earliest decline, with a precipitous drop between 45 and 52 years, when menopause typically begins. Aβ-CD4see requires a standard blood draw and provides a minimally invasive approach for assessing changes in Aβ biology that may reveal AD-related changes in physiology by a decade. Furthermore, CD4see probes can be modified to target any peptide, providing a powerful new tool to isolate antigen-specific CD4+ T cells from human subjects.

A novel Aβ-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer's disease mice.

Many Alzheimer's disease (AD) patients suffer from cerebrovascular abnormalities such as altered cerebral blood flow and cerebral microinfarcts. Recently, fibrinogen has been identified as a strong cerebrovascular risk factor in AD, as it specifically binds to β-amyloid (Aβ), thereby altering fibrin clot structure and delaying clot degradation. To determine if the Aβ-fibrinogen interaction could be targeted as a potential new treatment for AD, we designed a high-throughput screen and identified RU-505 as an effective inhibitor of the Aβ-fibrinogen interaction. RU-505 restored Aβ-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Furthermore, long-term treatment of RU-505 significantly reduced vascular amyloid deposition and microgliosis in the cortex and improved cognitive impairment in mouse models of AD. Our studies suggest that inhibitors targeting the Aβ-fibrinogen interaction show promise as therapy for treating AD.

Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal-regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood-brain barrier breakdown and white matter lesions. A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCAS-induced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1(-/-)) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-α expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1(-/-) mice. BCAS decreased claudin-5 expression and disrupted blood-brain barrier in the corpus callosum of wild-type but not ASK1(-/-) mice. Cerebral nitrotyrosine was increased in wild-type and ASK1(-/-) BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-α stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1(-/-) mice. Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through blood-brain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion-induced cognitive impairment.

Regulation of STAT3 by miR-106a is linked to cognitive impairment in ovariectomized mice

MicroRNAs are abundantly expressed in the brain and play an important role in disorders of the brain, including cognitive impairment and Alzheimer's disease (AD). A growing body of evidence suggests that the janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a key role in the pathogenesis of AD. However, it is unclear whether miRNAs are involved in this process. Therefore, we characterized the expression and role of miR-106a and JAK/STAT signaling in an ovariectomized (OVX) mouse model of cognitive impairment. Cognitive impairment, as indicated by escape latency and time spent in the platform quadrant in the Morris water maze test, was significantly reduced at 12 weeks post-OVX, compared to age-matched controls. Quantitative real-time PCR and Western blotting demonstrated that miR-106a was upregulated, and STAT3 and phospho-STAT3 were downregulated in the hippocampus at 12 weeks post-OVX, compared with age matched controls and the 6 and 8 weeks post-OVX groups. Transfection of human neuroblastoma SH-SY5Y cells with a miR-106a mimic reduced the expression of STAT3 mRNA, compared to control cells transfected with a scrambled mimic. STAT3 and phospho-STAT3 protein expression was upregulated or downregulated by a miR-106a inhibitor or miR-106a mimic, respectively, indicating that miR-106a negatively regulates STAT3. Luciferase reporter gene assays confirmed that miR-106a directly targets the 3′ untranslated region (UTR) of STAT3. This study suggests that miR-106a negatively regulates STAT3 activation, and also that miR-106a may provide a marker of onset or potential therapeutic target for cognitive disturbances.

Aβ-Degrading Enzymes: Potential for Treatment of Alzheimer Disease

There is increasing evidence that deficient clearance of β-amyloid (Aβ) contributes to its accumulation in late-onset Alzheimer disease (AD). Several Aβ-degrading enzymes, including neprilysin (NEP), insulin-degrading enzyme, and endothelin-converting enzyme reduce Aβ levels and protect against cognitive impairment in mouse models of AD. The activity of several Aβ-degrading enzymes rises with age and increases still further in AD, perhaps as a physiological response to minimize the buildup of Aβ. The age- and disease-related changes in expression of more recently recognized Aβ-degrading enzymes (e.g. NEP-2 and cathepsin B) remain to be investigated, and there is strong evidence that reduced NEP activity contributes to the development of cerebral amyloid angiopathy. Regardless of the role of Aβ-degrading enzymes in the development of AD, experimental data indicate that increasing the activity of these enzymes (NEP in particular) has therapeutic potential in AD, although targeting their delivery to the brain remains a major challenge. The most promising current approaches include the peripheral administration of agents that enhance the activity of Aβ-degrading enzymes and the direct intracerebral delivery of NEP by convection-enhanced delivery. In the longer term, genetic approaches to increasing the intracerebral expression of NEP or other Aβ-degrading enzymes may offer advantages.

Perindopril, a centrally active angiotensin‐converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer's disease

The purpose of this work was to test whether brain-penetrating angiotensin-converting enzyme (ACE) inhibitors (e.g., perindopril), as opposed to non-brain-penetrating ACE inhibitors (e.g., enalapril and imidapril), may reduce the cognitive decline and brain injury in Alzheimer's disease (AD). We first compared the effect of perindopril, enalapril, and imidapril on cognitive impairment and brain injury in a mouse model of AD induced by intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)₁₋₄₀. Perindopril, with significant inhibition of hippocampal ACE, significantly prevented cognitive impairment in this AD mouse model. This beneficial effect was attributed to the suppression of microglia/astrocyte activation and the attenuation of oxidative stress caused by iNOS induction and extracellular superoxide dismutase down-regulation. In contrast, neither enalapril nor imidapril prevented cognitive impairment and brain injury in this AD mouse. We next examined the protective effects of perindopril on cognitive impairment in PS2APP-transgenic mice overexpressing Aβ in the brain. Perindopril, without affecting brain Aβ deposition, significantly suppressed the increase in hippocampal ACE activity and improved cognition in PS2APP-transgenic mice, being associated with the suppression of hippocampal astrocyte activation and attenuation of superoxide. Our data demonstrated that the brain-penetrating ACE inhibitor perindopril, as compared to non-brain-penetrating ACE inhibitors, protected against cognitive impairment and brain injury in experimental AD models.