APP Transgenic Mouse Model Research Articles

Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease

Neuropeptide Y (NPY) is one of the most abundant protein transmitters in the central nervous system with roles in a variety of biological functions including: food intake, cardiovascular regulation, cognition, seizure activity, circadian rhythms, and neurogenesis. Reduced NPY and NPY receptor expression is associated with numerous neurodegenerative disorders including Alzheimer disease (AD). To determine whether replacement of NPY could ameliorate some of the neurodegenerative and behavioral pathology associated with AD, we generated a lentiviral vector expressing NPY fused to a brain transport peptide (apoB) for widespread CNS delivery in an APP-transgenic (tg) mouse model of AD. The recombinant NPY-apoB effectively reversed neurodegenerative pathology and behavioral deficits although it had no effect on accumulation of Aβ. The subgranular zone of the hippocampus showed a significant increase in proliferation of neural precursor cells without further differentiation into neurons. The neuroprotective and neurogenic effects of NPY-apoB appeared to involve signaling via ERK and Akt through the NPY R1 and NPY R2 receptors. Thus, widespread CNS-targeted delivery of NPY appears to be effective at reversing the neuronal and glial pathology associated with Aβ accumulation while also increasing NPC proliferation. Overall, increased delivery of NPY to the CNS for AD might be an effective therapy especially if combined with an anti-Aβ therapeutic.

Reduced β-amyloid pathology in an APP transgenic mouse model of Alzheimer's disease lacking functional B and T cells.

IntroductionIn Alzheimer’s disease, accumulation and pathological aggregation of amyloid β-peptide is accompanied by the induction of complex immune responses, which have been attributed both beneficial and detrimental properties. Such responses implicate various cell types of the innate and adaptive arm of the immunesystem, both inside the central nervous system, and in the periphery. To investigate the role of the adaptive immune system in brain β-amyloidosis, PSAPP transgenic mice, an established mouse model of Alzheimer’s disease, were crossbred with the recombination activating gene-2 knockout (Rag2 ko) mice lacking functional B and T cells. In a second experimental paradigm, aged PSAPP mice were reconstituted with bone marrow cells from either Rag2 ko or wildtype control mice.ResultsAnalyses from both experimental approaches revealed reduced β-amyloid pathology and decreased brain amyloid β-peptide levels in PSAPP mice lacking functional adaptive immune cells. The decrease in brain β-amyloid pathology was associated with enhanced microgliosis and increased phagocytosis of amyloid β-peptide aggregates.ConclusionThe results of this study demonstrate an impact of the adaptive immunity on cerebral β-amyloid pathology in vivo and suggest an influence on microglia-mediated amyloid β-peptide clearance as a possible underlying mechanism.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0251-x) contains supplementary material, which is available to authorized users.

Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models.

IntroductionAmyloid β (Aβ) accumulates in the extracellular space as diffuse and neuritic plaques in Alzheimer’s disease (AD). Aβ also deposits on the walls of arterioles as cerebral amyloid angiopathy (CAA) in most cases of AD and sometimes independently of AD. Apolipoprotein E (apoE) ɛ4 is associated with increases in both Aβ plaques and CAA in humans. Studies in mouse models that develop Aβ deposition have shown that murine apoE and human apoE4 have different abilities to facilitate plaque or CAA formation when studied independently. To better understand and compare the effects of murine apoE and human apoE4, we bred 5XFAD (line 7031) transgenic mice so that they expressed one copy of murine apoE and one copy of human apoE4 under the control of the normal murine apoE regulatory elements (5XFAD/apoEm/4). ResultsThe 5XFAD/apoEm/4 mice contained levels of parenchymal CAA that were intermediate between 5XFAD/apoEm/m and 5XFAD/apoE4/4 mice. In 5XFAD/apoEm/4 mice, we found that Aβ parenchymal plaques co-localized with much more apoE than did parenchymal CAA, suggesting differential co-aggregation of apoE with Aβ in plaques versus CAA. More importantly, within the brain parenchyma of the 5XFAD/apoEm/4 mice, plaques contained more murine apoE, which on its own results in more pronounced and earlier plaque formation, while CAA contained more human apoE4 which on its own results in more pronounced CAA formation. We further confirmed the co-aggregation of mouse apoE with Aβ in plaques by showing a strong correlation between insoluble mouse apoE and insoluble Aβ in PS1APP-21/apoEm/4 mice which develop plaques without CAA.ConclusionsThese studies suggest that both murine apoE and human apoE4 facilitate differential opposing effects in influencing Aβ plaques versus CAA via different co-aggregation with these two amyloid lesions and set the stage for understanding these effects at a molecular level.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0250-y) contains supplementary material, which is available to authorized users.

A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice.

BackgroundAlzheimer’s disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-β (Aβ) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aβ via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (β-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aβ. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans.ResultsTreatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aβ deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aβ was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared.ConclusionsIn a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-β deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer’s disease.

Early intraneuronal Abeta deposition in the hippocampus of APP transgenic mice.

Increasing evidence suggests that intraneuronal amyloid-beta (Abeta) accumulation may be an early event in Alzheimer's disease (AD) pathogenesis. However direct in vivo evidence regarding initial Abeta seeding is missing. Using an APP transgenic mouse model, our sensitive immunocytochemical procedures revealed a novel intraneuronal Abeta deposition in the somas of hippocampal CA1/subiculum neurons far in advance of the occurrence of extracellular Abetaplaques. These deposits increased exponentially with age and were elevated approximately 4-fold (p < 0.001) by high fat/high cholesterol diet. Abeta40 and Abeta42 were the major constituents of these deposits and were co-localized with lysosomal markers. Our results are consistent with the notion that the earliest Abeta deposition occurs intraneuronally, prior to extracellular amyloid plaque formation.

Progression of Seed-Induced Aβ Deposition within the Limbic Connectome.

An important early event in the pathogenesis of Alzheimer's disease (AD) is the aberrant polymerization and extracellular accumulation of amyloid-β peptide (Aβ). In young transgenic mice expressing the human Aβ-precursor protein (APP), deposits of Aβ can be induced by the inoculation of minute amounts of brain extract containing Aβ aggregates ("Aβ seeds"), indicative of a prion-like seeding phenomenon. Moreover, focal intracerebral injection of Aβ seeds can induce deposits not only in the immediate vicinity of the injection site, but, with time, also in distal regions of the brain. However, it remains uncertain whether the spatial progression of Aβ deposits occurs via nonsystematic diffusion from the injection site to proximal regions or via directed transit along neuroanatomical pathways. To address this question, we analyzed the spatiotemporal emergence of Aβ deposits in two different APP-transgenic mouse models that had been previously inoculated with Aβ seeds into the hippocampal formation. The results revealed a specific, neuroanatomically constrained pattern of induced Aβ deposits in structures corresponding to the limbic connectome, supporting the hypothesis that neuronal pathways act as conduits for the movement of proteopathic agents among brain regions, thereby facilitating the progression of disease.

Effects of CD2-associated protein deficiency on amyloid-β in neuroblastoma cells and in an APP transgenic mouse model.

BackgroundCD2-associated protein (CD2AP) is an SH3-containing scaffold adaptor protein which regulates the actin cytoskeleton. Recently, CD2AP was identified as a genetic risk factor for Alzheimer’s disease (AD) by several genome-wide association studies. One of the hallmarks of AD is the accumulation of aggregated forms of Amyloid-β (Aβ) in the brain. In humans, CD2AP AD susceptibility locus (rs9349407) is associated with an increased plaque burden. Aβ production is highly regulated by endocytosis and is influenced by lysosomal function. Lysosomal trafficking is influenced by CD2AP. In this study, we decreased CD2AP levels in N2a neuroblastoma cultures and PS1APP mice and analyzed Aβ levels and plaque burden.ResultsOur data show that suppressing CD2AP expression using shRNA in N2a-APP695 cells results in decreased cell membrane amyloid precursor protein, decreased Aβ release and a lower Aβ42/Aβ40 ratio. CD2AP protein is expressed in the brain as detected by western blot, and the expression level is dependent on gene dosage. In 1-month old PS1APP mice, complete loss of CD2AP in brain resulted in a decreased Aβ42/Aβ40 ratio in brain tissue lysates while there was no effect on Aβ deposition or accumulation in PS1APP mice expressing one copy of CD2AP.ConclusionCD2-Associated Protein affects Aβ levels and Aβ42/Aβ40 ratio in vitro. The effect of CD2-Associated Protein on Aβ metabolism is subtle in vivo.

IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior

Anti-inflammatory strategies are proposed to have beneficial effects in Alzheimer's disease. To explore how anti-inflammatory cytokine signaling affects Aβ pathology, we investigated the effects of adeno-associated virus (AAV2/1)-mediated expression of Interleukin (IL)-10 in the brains of APP transgenic mouse models. IL-10 expression resulted in increased Aβ accumulation and impaired memory in APP mice. A focused transcriptome analysis revealed changes consistent with enhanced IL-10 signaling and increased ApoE expression in IL-10-expressing APP mice. ApoE protein was selectively increased in the plaque-associated insoluble cellular fraction, likely because of direct interaction with aggregated Aβ in the IL-10-expressing APP mice. Ex vivo studies also show that IL-10 and ApoE can individually impair glial Aβ phagocytosis. Our observations that IL-10 has an unexpected negative effect on Aβ proteostasis and cognition in APP mouse models demonstrate the complex interplay between innate immunity and proteostasis in neurodegenerative diseases, an interaction we call immunoproteostasis.

Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-β in an APP transgenic mouse model.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impairment of cognitive function, extracellular amyloid plaques, intracellular neurofibrillary tangles, and synaptic and neuronal loss. There is substantial evidence that the aggregation of amyloid β (Aβ) in the brain plays a key role in the pathogenesis of AD and that Aβ aggregation is a concentration dependent process. Recently, it was found that Aβ levels in the brain interstitial fluid (ISF) are regulated by the sleep-wake cycle in both humans and mice; ISF Aβ is higher during wakefulness and lower during sleep. Intracerebroventricular infusion of orexin increased wakefulness and ISF Aβ levels, and chronic sleep deprivation significantly increased Aβ plaque formation in amyloid precursor protein transgenic (APP) mice. Growth hormone-releasing hormone (GHRH) is a well-documented sleep regulatory substance which promotes non-rapid eye movement sleep. GHRHR(lit/lit) mice that lack functional GHRH receptor have shorter sleep duration and longer wakefulness during light periods. The current study was undertaken to determine whether manipulating sleep by interfering with GHRH signaling affects brain ISF Aβ levels in APPswe/PS1ΔE9 (PS1APP) transgenic mice that overexpress mutant forms of APP and PSEN1 that cause autosomal dominant AD. We found that intraperitoneal injection of GHRH at dark onset increased sleep and decreased ISF Aβ and that delivery of a GHRH antagonist via reverse-microdialysis suppressed sleep and increased ISF Aβ. The diurnal fluctuation of ISF Aβ in PS1APP/GHRHR(lit/lit) mice was significantly smaller than that in PS1APP/GHRHR(lit/+) mice. However despite decreased sleep in GHRHR deficient mice, this was not associated with an increase in Aβ accumulation later in life. One of several possibilities for the finding is the fact that GHRHR deficient mice have GHRH-dependent but sleep-independent factors which protect against Aβ deposition.

A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease.

In 1906, Alois Alzheimer described the neuropathology of the disease that was to bear his name. Subsequently, our understanding of Alzheimer disease (AD) has grown significantly. The autosomal dominant mutations to the amyloid precursor protein (APP), presenilin (PS) 1, and PS2 genes that cause early onset AD have been very informative, leading to the articulation of the amyloid cascade hypothesis. This hypothesis has been the basis for several disease-modifying therapeutic approaches for AD. This has been partly because it provided a coherent framework for understanding AD pathogenesis but also because several pharmacological approaches that targeted the amyloid peptide (amyloidocentric) were sufficiently well-founded scientifically to enter clinical development. In the past 5 years, there have been 6 amyloidocentric programs that completed phase 3 clinical testing. None met their primary outcome measures (Table 1), although 1, solanezumab, showed encouraging results in a prespecified secondary outcome measure. This disappointing track record has brought into question the amyloidocentric therapeutic approach. This review will consider these programs from the following perspectives:

Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IκBα.

Tumor necrosis factor receptor II (TNFRII) is one of the TNF receptor superfamily members and our recent pathological studies show that TNFRII is deficient in the brains of Alzheimer's disease (AD). However, the mechanisms of TNFRII in AD pathogenesis remain unclear. In the present study, by using the gene-targeting approach to delete TNFRII in AD transgenic mouse model, we found that, in the brain of APP23 mice with TNFRII deletion (APP23/TNFRII(-/-)), AD-like pathology, i.e. plaque formation and microglial activation, occurs as early as 6 months of age. To test whether the increased levels of Aβ plaques was due to elevated Aβ, we measured Aβ and found that Aβ levels indeed were significantly increased at this age. Because β-secretase, BACE1, is critical enzyme for Aβ production, we have examined BACE1 and found that BACE1 is increased in both protein levels and enzymatic activity as early as 6 months of age; Having shown that BACE1 promoter region contains NF-κB binding sites, we found that cytoplasmic NF-κB was elevated and SUMO1 binding to IκBα was decreased. To further verify these findings, we have overexpressed TNFRII and identified that overexpressing TNFRII can reverse the findings from APP23/TNFRII(-/-) mice. Altogether, our results demonstrate novel roles of TNFRII in the regulation of Aβ production, suggesting a potential therapeutic strategy for AD by up-regulating TNFRII levels and elevating phosphorylated IκBα by SUMOylation.

Cholinergic dysregulation in prodromal Alzheimer’s disease

The cholinergic hypothesis of geriatric memory dysfunction led to the development of FDA-approved anticholinesterase drugs to maintain this system in AD patients. The importance of defining the status of the cholinergic basal forebrain cortical projection system in subjects with prodromal AD who are at risk for developing AD continues to be of great clinical and translational interest. The findings presented are derived from molecular and cellular neuropathologic investigations of people who died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and Alzheimer's disease (AD) as well as from AD transgenic animal studies. Clinical pathologic investigations revealed that CBF neurons maintain their cholinergic neuronal phenotype despite exhibiting pretangles, which correlate with cognitive impairment and an altered ratio of 3 repeat to 4 repeat tau in the MCI brain. Interestingly, the cortical cholinergic system displays an upregulation of choline acetyltransferease (ChAT) activity in the frontal cortex and hippocampus suggesting early reparative mechanisms during prodromal AD. Moreover, despite the early accumulation of amyloid burden in the precuneus component of the default memory network, cholinergic enzyme activity remains stable in MCI and only declines in clinical AD, when PiB binding and soluble beta-amyloid 42 levels are substantially elevated compared to MCI. Moreover, amyloid deposition failed to induce cholinergic cortical neuronal degeneration in APP and triple transgenic mouse models of AD. Increased cortical levels of proNGF and a decrease in TrkA suggest a shift away from cell survival to apoptotic proNGF signaling. Interestingly, this switch to cell death mechanisms did not occur in the hippocampus during prodromal AD. Together these data suggest that CBF system dysregulation is not uniform, the system is neuroplastic, pretangle pathology plays a key role in cognitive impairment, amyloid deposition may not be toxic early on and there is a shift from cell survival to cell death trophic factor signaling in MCI.

Tetrahydroxystilbene glucoside antagonizes age-related α-synuclein overexpression in the hippocampus of APP transgenic mouse model of Alzheimer's disease

To investigate the mRNA and protein alterations of α-synuclein in the brain of Alzheimer's disease-like mouse model at the different ages, and to evaluate the effects of 2,3,5,4'-tetrahydroxy stilbene-2-O-β-D-glucoside (TSG) on α-synuclein expression. TSG (120 or 240 μmol kg(-1)d(-1)) was intragastrically administered to APPV717I transgenic (Tg) mice at 4- or 10-month-old for 6 months. mRNA expression of α-synuclein increased in hippocampus in 4 month to 16 month old Tg mice compared with age-matched control. α-synuclein protein expression in hippocampus also increased in 4 month to 16 month old Tg mice significantly. Significant down-regulation of α-synuclein mRNA and protein expression in hippocampus was found after treatment of TSG for 6 months in both 10- and 16-month-old Tg mice. Production of dimer and tetramer of α-synuclein protein in Tg mice was inhibited after treatment with TSG. The expression and aggregation of α-synuclein was age-dependently increased in Tg mice. TSG not only prevents over-expression of α-synuclein at an early stage, but also reverses the increased expression of α-synuclein and inhibits the aggregation at the late stage of Tg mice. TSG may have potential to the prevention and treatment of Alzheimer's diseases.

Prazosin, an α1-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease

Noradrenergic deficits have been described in the hippocampus and the frontal cortex of Alzheimer's disease brains, which are secondary to locus coeruleus degeneration. Locus coeruleus is the brain stem nucleus responsible for synthesis of noradrenaline and from where all noradrenergic neurons project. In addition, it has been suggested that noradrenaline might play a role in modulating inflammatory responses in Alzheimer's disease. In this study we aimed to investigate the effect of various agonists and antagonists for adrenergic receptors on amyloid precursor protein processing. Among them, we found that prazosin, an α1-adrenoceptor antagonist, was able to reduce the generation of amyloid β in N2a cells. Treatment of transgenic APP23 mice with prazosin prevented memory deficits over time. Although prazosin did not influence amyloid plaque load, it induced astrocytic proliferation and increased the release of apolipoprotein E and anti-inflammatory cytokines. These findings suggest that chronic treatment with prazosin leads to an anti-inflammatory response with potential beneficial effects on cognitive performance.

P1‐218: Neuroprotective effects of a novel Aß‐protein stabilizer in APP transgenic mouse model of Alzheimer's disease

P1‐218: Neuroprotective effects of a novel Aß‐protein stabilizer in APP transgenic mouse model of Alzheimer's disease

Synergistic Effects of Antidementia Drugs on Spatial Learning and Recall in the APP23 Transgenic Mouse Model of Alzheimer's Disease

Current treatment of Alzheimer's disease rests on cholinergic and anti-glutamatergic substances. It has been suggested that acetylcholine is required for memory acquisition but is less important for memory retrieval. It was our goal to investigate the effects of treatment with donepezil, memantine, and a combination thereof on spatial memory. We assessed spatial memory of male wild type and B6C3-Tg(APPswe,PSEN1dE9)85Dbo (APP23) transgenic animals in a complex dry-land maze. Animals were treated with donepezil (1 mg/kg) and memantine (10 mg/kg). Total time to escape from the maze decreased in 4.5 month old sham-treated wild-type animals and, to a lesser extent, in APP23 animals. Analysis of time spent moving and resting revealed that the treatment effect is conferred by a reduction of the moving time for donepezil and a reduction of the resting time for memantine. Combination treatment with donepezil and memantine fostered a greater improvement than treatment with either substance alone. We conclude that enhancement of spatial learning in a dry-land maze on cholinergic or anti-glutamatergic treatment is differentially conferred during moving of the animals, possibly reflecting acquisition of spatial information, and resting of the animals, possibly reflecting retrieval of spatial information. Combination treatment with donepezil and memantine exerts a synergistic effect improving both moving time and resting time and thus possibly both spatial learning and retrieval.

Validation of the APP23 Transgenic Mouse Model of Alzheimer’s Disease through Evaluation of Risperidone Treatment on Aggressive Behaviour

Valid animal models are indispensable in the drug discovery pipeline for dementia. Transgenic APP23 mice model Alzheimer's disease patients' memory deficits and additionally present with various behavioural disturbances, such as aggressive behaviour. The present study investigated and confirmed significant sensitivity of the model to the aggression-lowering ability of the antipsychotic agent risperidone (CAS 106266-06-2). The sensitivity for such anti-aggressive action contributes to the therapeutic predictive validity of the APP23 model of Alzheimer's disease, which can be used as a pre-clinical screening tool for the identification of novel anti-aggressive agents.

VEGF-induced angiogenesis ameliorates the memory impairment in APP transgenic mouse model of Alzheimer’s disease

Vascular endothelial growth factor (VEGF) was investigated in the present study to see whether it could provide a therapeutic opportunity for the treatment of Alzheimer’s disease (AD). PDGF-hAPP V717I transgenic mice were treated with VEGF or PBS by intraperitoneal injection for three consecutive days. The results showed that VEGF ameliorated the memory impairment of mice, accompanied by CD34 + cells increasing in peripheral blood, vWF + vessels increasing in hippocampus, and CD34 +/VEGFR2 +, vWF +/VEGFR2 + and BrdU +/vWF + cells expressing in hippocampus. Furthermore, the level of choline acetyltransferase (ChAT) was considerably enhanced and Aβ deposition was decreased in the brains of mice upon VEGF treatment. These observations suggest that VEGF should be pursued as a novel therapeutic agent for treatment of AD.

Elevated levels of soluble, high molecular weight SDS-denaturable Aβ-aggregates are associated with dendritic degeneration in APP-transgenic mouse models

Elevated levels of soluble, high molecular weight SDS-denaturable Aβ-aggregates are associated with dendritic degeneration in APP-transgenic mouse models

Chronic Delivery of Antibody Fragments Using Immunoisolated Cell Implants as a Passive Vaccination Tool

BackgroundMonoclonal antibodies and antibody fragments are powerful biotherapeutics for various debilitating diseases. However, high production costs, functional limitations such as inadequate pharmacokinetics and tissue accessibility are the current principal disadvantages for broadening their use in clinic.Methodology and Principal FindingsWe report a novel method for the long-term delivery of antibody fragments. We designed an allogenous immunoisolated implant consisting of polymer encapsulated myoblasts engineered to chronically release scFv antibodies targeted against the N-terminus of the Aβ peptide. Following a 6-month intracerebral therapy we observed a significant reduction of the production and aggregation of the Aβ peptide in the APP23 transgenic mouse model of Alzheimer's disease. In addition, functional assessment showed prevention of behavioral deficits related to anxiety and memory traits.Conclusions and SignificanceThe chronic local release of antibodies using immunoisolated polymer cell implants represents an alternative passive vaccination strategy in Alzheimer's disease. This novel technique could potentially benefit other diseases presently treated by local and systemic antibody administration.