PDAPP Mice Research Articles

Long-term prevention of Alzheimer's disease-like behavioral deficits in PDAPP mice carrying a mutation in Asp664

The deficits of Alzheimer's disease (AD) are believed to result, at least in part, from neurotoxicity of β-amyloid (Aβ), a set of 38–43 amino acid fragments derived from the β-amyloid precursor protein (APP). In addition, APP generates the APP-C31 and Jcasp toxic fragments intracellularly by cleavage at Asp664. We reported that mutation of Asp664 to Ala in a FAD-human APP transgene prevented AD-like deficits but did not affect Aβ production or deposition in PDAPP mice, arguing that D664A plays a crucial role in the generation of AD-like deficits. Whether D664A simply delays or completely prevents AD-like deficits, however, remained undefined. To address this question, we performed behavioral studies longitudinally on a pretrained mouse cohort at 9 and 13 months (mo) of age. While behavioral deficits were present in PDAPP mice, performance of Tg PDAPP(D664A) mice was not significantly different from non-Tg littermates’ across all ages tested. Moreover, aberrant patterns in non-cognitive components of behavior in PDAPP mice were ameliorated in PDAPP(D664A) animals as well. A trend towards poorer retention at 9 mo and poorer learning at 13 mo that did not reach statistical significance was observed in PDAPP(D664A) mice. These results support and extend recent studies showing that cleavage of APP at Asp664 (or protein–protein interactions dependent on Asp664) is a crucial event in the generation of AD-like deficits in PDAPP mice. Our results thus further demonstrate that the D664A mutation either completely precludes, or markedly delays (beyond 13 mo) the appearance of AD-like deficits in this mouse model of AD.

FDG autoradiography reveals developmental and pathological effects of mutant amyloid in PDAPP transgenic mice

Transgenic mouse models of Alzheimer's disease (AD) show some characteristic features of the disease, and we aim to further bridge the gap between studies of humans with AD, those at risk, and these murine models by providing shared markers of disease which could be used to track progression and assess future interventions. Brain imaging measurements may prove useful in this regard. We previously found that the homozygous PDAPP mouse model of AD showed significant declines in glucose uptake with age in posterior cingulate cortex (PCC), an area homologous to the human posterior cingulate, which shows significant declines in AD and in those at risk for AD. To further evaluate this potential biomarker and its correlation across age, we used fluorodeoxyglucose (FDG) autoradiography at two ages (2 and 12 months) in wildtype, heterozygous, and homozygous PDAPP mice. We found significant posterior cingulate fluorodeoxyglucose uptake declines again in homozygous PDAPP mice, but at both ages assessed. There was a strong effect of gene dose; homozygous mice showed larger and earlier effects. These results, in conjunction with our previous analyses, indicate a nonlinear progression stemming from synergistic effects of the overexpressed mutant gene, both developmental and pathological. The posterior cingulate is preferentially vulnerable to both effects of transgene in the PDAPP mouse, and both are independent of amyloid deposition.

Signal transduction in Alzheimer disease: p21‐activated kinase signaling requires C‐terminal cleavage of APP at Asp664

The deficits in Alzheimer disease (AD) stem at least partly from neurotoxic beta-amyloid peptides generated from the amyloid precursor protein (APP). APP may also be cleaved intracellularly at Asp664 to yield a second neurotoxic peptide, C31. Previously, we showed that cleavage of APP at the C-terminus is required for the impairments seen in APP transgenic mice, by comparing elements of the disease in animals modeling AD, with (platelet-derived growth factor B-chain promoter-driven APP transgenic mice; PDAPP) versus without (PDAPP D664A) a functional Asp664 caspase cleavage site. However, the signaling mechanism(s) by which Asp664 contributes to these deficits remains to be elucidated. In this study, we identify a kinase protein, recently shown to bind APP at the C-terminus and to contribute to AD, whose activity is modified in PDAPP mice, but normalized in PDAPP D664A mice. Specifically, we observed a significant increase in nuclear p21-activated kinase (isoforms 1, 2, and or 3; PAK-1/2/3) activation in hippocampus of 3 month old PDAPP mice compared with non-transgenic littermates, an effect completely prevented in PDAPP D664A mice. In contrast, 13 month old PDAPP mice displayed a significant decrease in PAK-1/2/3 activity, which was once again absent in PDAPP D664A mice. Similarly, in hippocampus of early and severe AD subjects, there was a progressive and subcellular-specific reduction in active PAK-1/2/3 compared with normal controls. Interestingly, total PAK-1/2/3 protein was increased in early AD subjects, but declined in moderate AD and declined further, to significantly below that of control levels, in severe AD. These findings are compatible with previous suggestions that PAK may be involved in the pathophysiology of AD, and demonstrate that both early activation and late inactivation in the murine AD model require the cleavage of APP at Asp664.

Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease

APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1(-/-) mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe(-/-) mice: there was significantly less amyloid beta-peptide (Abeta) deposition, a redistribution of Abeta to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S-positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.

Impaired Spine Stability Underlies Plaque-Related Spine Loss in an Alzheimer's Disease Mouse Model

Dendritic spines, the site of most excitatory synapses in the brain, are lost in Alzheimer's disease and in related mouse models, undoubtedly contributing to cognitive dysfunction. We hypothesized that spine loss results from plaque-associated alterations of spine stability, causing an imbalance in spine formation and elimination. To investigate effects of plaques on spine stability in vivo, we observed cortical neurons using multiphoton microscopy in a mouse model of amyloid pathology before and after extensive plaque deposition. We also observed age-matched nontransgenic mice to study normal effects of aging on spine plasticity. We found that spine density and structural plasticity are maintained during normal aging. Tg2576 mice had normal spine density and plasticity before plaques appeared, but after amyloid pathology is established, severe disruptions were observed. In control animals, spine formation and elimination were equivalent over 1 hour of observation ( approximately 5% of observed spines), resulting in stable spine density. However, in aged Tg2576 mice spine elimination increased, specifically in the immediate vicinity of plaques. Spine formation was unchanged, resulting in spine loss. These data show a small population of rapidly changing spines in adult and even elderly mouse cortex; further, in the vicinity of amyloid plaques, spine stability is markedly impaired leading to loss of synaptic structural integrity.

Gene expression profile of the PDAPP mouse model for Alzheimer's disease with and without Apolipoprotein E

The APOE ɛ4 allele is a strong risk factor for Alzheimer's disease (AD). However, the molecular basis for this effect remains unclear. We examined expression of approximately 12,000 genes and expressed sequence tags in the hippocampus and cortex of PDAPP (APP V717) mice modeling AD that show extensive amyloid beta (Aβ) deposition, and in PDAPP mice lacking murine APOE expression, which show marked attenuation of Aβ deposition in the brain. Wild type and APOE knockout animals were also examined. Expression levels were determined at the initial stage of Aβ deposition, as well as in older animals showing extensive neuropathological changes. Fifty-four transcripts were identified using our statistical analysis as differentially regulated between the PDAPP and PDAPP/APOE ko mice, whereas 31 transcripts were classified as differentially regulated among PDAPP mice and WT animals, and seven transcripts were identified as regulated between the PDAPP/APOE ko animals and the APOE ko animals. Interestingly, many of the differentially regulated genes we detected can be related to biological processes previously shown to be important in AD pathophysiology, including inflammation, calcium homeostasis, cholesterol transport and uptake, kinases and phosphatases involved in tau phosphorylation and dephosphorylation, mitochondrial energy metabolism, protein degradation, neuronal growth, endoplasmic reticulum (ER) stress related proteins, antioxidant activity, cytoskeletal organization, and presenilin binding proteins. Regulated genes also included some not directly associated with AD in the past but likely to be involved in known AD pathophysiologic mechanisms, and others that may represent completely novel factors in the pathogenesis of AD. These results provide a global molecular profile of hippocampal and cortical gene expression during the initial and intermediate stages Aβ deposition, and the effects of APOE deletion on this process.

Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice

The aspartyl protease beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates processing of amyloid precursor protein (APP) into amyloid beta (Abeta) peptide, the major component of Alzheimer disease (AD) plaques. To determine the role that BACE1 plays in the development of Abeta-driven AD-like pathology, we have crossed PDAPP mice, a transgenic mouse model of AD overexpressing human mutated APP, onto mice with either a homozygous or heterozygous BACE1 gene knockout. Analysis of PDAPP/BACE(-/-) mice demonstrated that BACE1 is absolutely required for both Abeta generation and the development of age-associated plaque pathology. Furthermore, synaptic deficits, a neurodegenerative pathology characteristic of AD, were also reversed in the bigenic mice. To determine the extent of BACE1 reduction required to significantly inhibit pathology, PDAPP mice having a heterozygous BACE1 gene knock-out were evaluated for Abeta generation and for the development of pathology. Although the 50% reduction in BACE1 enzyme levels caused only a 12% decrease in Abeta levels in young mice, it nonetheless resulted in a dramatic reduction in Abeta plaques, neuritic burden, and synaptic deficits in older mice. Quantitative analyses indicate that brain Abeta levels in young APP transgenic mice are not the sole determinant for the changes in plaque pathology mediated by reduced BACE1. These observations demonstrate that partial reductions of BACE1 enzyme activity and concomitant Abeta levels lead to dramatic inhibition of Abeta-driven AD-like pathology, making BACE1 an excellent target for therapeutic intervention in AD.

Active β-Amyloid Immunization Restores Spatial Learning in PDAPP Mice Displaying Very Low Levels of β-Amyloid

The behavioral and biochemical impact of active immunization against human beta-amyloid (Abeta) was assessed using male transgenic (Tg) mice overexpressing a human mutant amyloid precursor protein (heterozygous PDAPP mice) and littermate controls. Administration of aggregated Abeta42 occurred at monthly intervals from 7 months ("prevention") or 11 months ("reversal"), followed by double-blind behavioral training at 16 months on a cued task, then serial spatial learning in a water maze. Using a 2 x 2 design, with Abeta42 adjuvanted with MPL-AF (adjuvant formulation of monophosphoryl lipid A) or MPL-AF alone, PDAPP mice were impaired compared with non-Tg littermates on two separate measures of serial spatial learning. Immunization caused no overall rescue of learning but limited the accumulation of total Abeta and Abeta42 levels in cortex and hippocampus by up to 60%. In immunized PDAPP mice, significant negative correlations were observed between hippocampal and cortical Abeta levels and learning capacity, particularly in the prevention study, and correlations between learning capacity and antibody titer. Moreover, a subset of PDAPP mice with very low Abeta levels (hippocampal Abeta levels of <6000 ng/g or cortical Abeta levels of <1000 ng/g) was indistinguishable from non-Tg controls. Mice in the prevention study were also rescued from cognitive impairment more effectively than those in the reversal study. The combination of variability in antibody response and differential levels of Abeta accumulation across the population of immunized PDAPP mice may be responsible for success in cognitive protection with only a subset of these animals, but the similarity to the findings of certain human vaccination trials is noteworthy.

Apolipoprotein E and Low Density Lipoprotein Receptor-related Protein Facilitate Intraneuronal Aβ42 Accumulation in Amyloid Model Mice

The low density lipoprotein receptor-related protein (LRP) is highly expressed in the brain and has been shown to alter the metabolism of amyloid precursor protein and amyloid-beta peptide (Abeta) in vitro. Previously we developed mice that overexpress a functional LRP minireceptor (mLRP2) in their brains and crossed them to the PDAPP mouse model of Alzheimer disease. Overexpression of mLRP2 in 22-month-old PDAPP mice with amyloid plaques increased a pool of carbonate-soluble Abeta in the brain and worsened memory-related behavior. In the current study, we examined the effects of mLRP2 overexpression on 3-month-old PDAPP mice that had not yet developed amyloid plaques. We found significantly higher levels of membrane-associated Abeta42 in the hippocampus of mice that overexpressed mLRP2. Using immunohistochemical methods, we observed significant intraneuronal Abeta42 in the hippocampus and frontal cortex of PDAPP mice, which frequently co-localized with the lysosomal marker LAMP-1. Interestingly, PDAPP mice lacking apolipoprotein E (apoE) had much less intraneuronal Abeta42. We also found that PC12 cells overexpressing mLRP2 cleared Abeta42 and Abeta40 more rapidly from media than PC12 cells transfected with the vector only. Preincubation of apoE3 or apoE4 with Abeta42 increased the rate of Abeta clearance, and this effect was partially blocked by receptor-associated protein. Our results support the hypothesis that LRP binds and endocytoses Abeta42 both directly and via apoE but that endocytosed Abeta42 is not completely degraded and accumulates in intraneuronal lysosomes.

P4-312: A model-based comparison of the nonclinical and clinical effects of anti-Aβ antibodies on plasma Aβ1-40 levels

Administration of anti–Aβ antibodies to animals and humans produces increases in the total levels of Aβ in the plasma. This biomarker response provides evidence that the antibodies ‘hit the target’ and also provides insight for comparison of effects between species. Although difficult to measure directly, an understanding of antibody effects on ‘free’ Aβ levels would also be advantageous, as one of the desired effects of antibody administration is to decrease ‘free’ Aβ levels and shift Aβ equilibria away from deposition into plaque. Mechanism–based pharmacokinetic/pharmacodynamic (PK/PD) models were developed to characterize relationships between plasma anti–Aβ antibody levels and the time–course of the plasma Aβ1–40 response in PDAPP mice and Alzheimer's patients. These models allow inference of effects on both ‘total’ and ‘free’ Aβ. Simulations were performed to compare the relative biomarker responses in PDAPP mice and humans. Following intraperitoneal administration of anti–Aβ antibodies (m266) to PDAPP mice, plasma m266 concentrations showed first–order absorption followed by mono–exponential decay. In humans, intravenous anti–Aβ antibody administration led to bi–exponential pharmacokinetics that were well characterized using a 2–compartment PK model. In both mice and humans, antibody concentrations appeared to increase proportionally with administered dose. Dose–dependant plasma Aβ1–40 pharmacodynamic responses were observed in both mice and humans. These PD responses were well characterized using mechanism–based PK/PD models that incorporated antibody–antigen binding principles. Simulation results showed greater effects on ‘free’ Aβ1–40 at the dose levels administered in humans than for the dose levels used for nonclinical efficacy studies in PDAPP mice. This analysis illustrates that the dose levels studied in the initial clinical study compare favorably, from a biomarker perspective, with dose levels that demonstrated beneficial effects in PDAPP mice.

P4-271: Bace inhibitor in vivo proof-of-concept studies in PDAPP mice

P4-271: Bace inhibitor in vivo proof-of-concept studies in PDAPP mice

O1-06-07: Immunotherapy with antibodies to N-terminal amyloid-β peptides reduces cerebral amyloid angiopathy in PDAPP mice

Passive immunotherapy with amyloid–β (Aβ) antibodies reduces a number of AD pathologies including parenchymal Aβ plaques, neuritic dystrophy, synaptic loss, and memory function in mouse models, and many of these effects are beginning to be seen in AD patients. In addition to parenchymal deposition of amyloid, AD is also characterized by amyloid fibrils in the cerebral vasculature in the majority of patients, a condition called cerebral amyloid angiopathy (CAA). Previous studies have suggested that immunotherapy does not clear and may increase CAA and the incidence of microhemorrhage. In the present study we demonstrate that certain immunotherapies are surprisingly highly efficacious in removing CAA and that the incidence of microhemorrhage can be modulated by dosage. We examined the effects of passive immunization on CAA in 2 PDAPP mouse studies: one a comparison of antibodies to different Aβ epitopes (3D6, Aβ1–5; 12A11 and 10D5, Aβ3–7; 266 Aβ16–23) at one dose, and a 3D6 dose–response study at 3 doses. CAA clearance and microhemorrhage incidence were assessed after 6 months using Aβ IHC and hemosiderin detection. We found that 3D6 at the highest dose completely cleared CAA, with nearly 100% clearance observed in both studies. In addition, partial clearance was evident at both lower doses as well as with 10D5 and 12A11 treatments. 266 showed no effect on CAA or plaque clearance. Sites of hemosiderin staining were limited to focal, perivascular regions and were almost entirely restricted to meningeal vasculature and sagittal sinus vessels. Lower dose 3D6 groups had significantly reduced hemosiderin ratings compared to the highest dose group, and the 266 and 10D5 groups did not significantly differ from the control. Hemosiderin staining co–localized with Aβ at sites of ongoing clearance in the lower dose 3D6, 12A11, and 10D5 groups. Collectively, these observations showed that removal of CAA at lower doses of 3D6 minimized microhemorrhage over the 6–month study period. These observations suggest that passive immunization can reduce CAA, and modulating antibody dose and duration can significantly mitigate the incidence of microhemorrhage. Immunotherapy can then potentially remove or reverse the CAA that is thought to lead to dysfunction of the microvasculature in AD.

P4-293: Evidence for an age dependent rate limiting pool of CNS Aβ in PDAPP mouse altered by Aβ antibody administration

P4-293: Evidence for an age dependent rate limiting pool of CNS Aβ in PDAPP mouse altered by Aβ antibody administration

Nonprogressive transgene-related callosal and hippocampal changes in PDAPP mice

We have previously shown that homozygous PDAPP mice, a transgenic model of Alzheimer's-like amyloidosis, have abnormal corpus callosi and anterior hippocampi. Now, we investigated the extent to which these morphological abnormalities are correlated with mutant gene dose in a larger, independent, and substantially younger cohort. Homozygous and heterozygous PDAPP mice had significantly smaller callosal commissure length and anterior hippocampal area than controls. Reductions correlated with mutant APP gene dose, with homozygotes showing the greatest reduction, and were present at 2 months of age. These findings and previous work with APP knockouts suggest that PDAPP mice have impaired white matter development due to interference with native murine APP.

Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A antibody

Disruption of cholinergic neurotransmission contributes to the memory impairment that characterizes Alzheimer disease (AD). Since the amyloid cascade hypothesis of AD pathogenesis postulates that amyloid beta (A beta) peptide accumulation in critical brain regions also contributes to memory impairment, we assessed cholinergic function in transgenic mice where the human A beta peptide is overexpressed. We first measured hippocampal acetylcholine (ACh) release in young, freely moving PDAPP mice, a well-characterized transgenic mouse model of AD, and found marked A beta-dependent alterations in both basal and evoked ACh release compared with WT controls. We also found that A beta could directly interact with the high-affinity choline transporter which may impair steady-state and on-demand ACh release. Treatment of PDAPP mice with the anti-A beta antibody m266 rapidly and completely restored hippocampal ACh release and high-affinity choline uptake while greatly reducing impaired habituation learning that is characteristic of these mice. Thus, soluble "cholinotoxic" species of the A beta peptide can directly impair cholinergic neurotransmission in PDAPP mice leading to memory impairment in the absence of overt neurodegeneration. Treatment with certain anti-A beta antibodies may therefore rapidly reverse this cholinergic dysfunction and relieve memory deficits associated with early AD.

Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease

Abnormal subgranular zone (SGZ) neurogenesis is proposed to contribute to Alzheimer's disease (AD)-related decreases in hippocampal function. Our goal was to examine hippocampal neurogenesis in the PDAPP mouse, a model of AD with age-dependent accumulation of amyloid-beta(42) (Abeta(42))-containing plaques that is well studied with regard to AD therapies. A secondary goal was to determine whether altered neurogenesis in the PDAPP mouse is associated with abnormal maturation or number of mature cells. A tertiary goal was to provide insight into why hippocampal neurogenesis appears to be increased in AD post-mortem tissue and decreased in most AD mouse models. We report an age-dependent decrease in SGZ proliferation in homozygous PDAPP mice. At 1 year of age, PDAPP mice also had new dentate gyrus granule neurons with abnormal maturation and fewer dying cells relative to control mice. In contrast to decreased SGZ cell birth, PDAPP mice had increased birth of immature neurons in the outer portion of the granule cell layer (oGCL), providing insight into why some studies link AD with increased neurogenesis. However, these ectopic oGCL cells were still rare compared with SGZ proliferating cells, emphasizing that the primary characteristic of PDAPP mice is decreased neurogenesis. The decrease in SGZ neurogenesis was not associated with an age-dependent loss of dentate granule neurons. The altered neurogenesis in the PDAPP mouse may contribute to the age-related cognitive deficits reported in this model of AD and may be a useful adjunct target for assessing the impact of AD therapies.

Deletion of Abca1 Increases Aβ Deposition in the PDAPP Transgenic Mouse Model of Alzheimer Disease

Apolipoprotein E (apoE) genotype has a major influence on the risk for Alzheimer disease (AD). Different apoE isoforms may alter AD pathogenesis via their interactions with the amyloid beta-peptide (Abeta). Mice lacking the lipid transporter ABCA1 were found to have markedly decreased levels and lipidation of apoE in the central nervous system. We hypothesized that if Abca1-/- mice were bred to the PDAPP mouse model of AD, PDAPP Abca1-/ mice would have a phenotype similar to that of PDAPP Apoe+/- and PDAPP Apoe-/- mice, which develop less amyloid deposition than PDAPP Apoe+/+ mice. In contrast to this prediction, 12-month-old PDAPP Abca -/- mice had significantly higher levels of hippocampal Abeta, and cerebral amyloid angiopathy was significantly more common compared with PDAPP Abca1+/+ mice. Amyloid precursor protein (APP) C-terminal fragments were not different between Abca1 genotypes prior to plaque deposition in 3-month-old PDAPP mice, suggesting that deletion of Abca1 did not affect APP processing or Abeta production. As expected, 3-month-old PDAPP Abca1-/- mice had decreased apoE levels, but they also had a higher percentage of carbonate-insoluble apoE, suggesting that poorly lipidated apoE is less soluble in vivo. We also found that 12-month-old PDAPP Abca1-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble Abeta. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo.

Defective Tumor Necrosis Factor-α-dependent Control of Astrocyte Glutamate Release in a Transgenic Mouse Model of Alzheimer Disease

The cytokine tumor necrosis factor-alpha (TNFalpha) induces Ca2+-dependent glutamate release from astrocytes via the downstream action of prostaglandin (PG) E2. By this process, astrocytes may participate in intercellular communication and neuromodulation. Acute inflammation in vitro, induced by adding reactive microglia to astrocyte cultures, enhances TNFalpha production and amplifies glutamate release, switching the pathway into a neurodamaging cascade (Bezzi, P., Domercq, M., Brambilla, L., Galli, R., Schols, D., De Clercq, E., Vescovi, A., Bagetta, G., Kollias, G., Meldolesi, J., and Volterra, A. (2001) Nat. Neurosci. 4, 702-710). Because glial inflammation is a component of Alzheimer disease (AD) and TNFalpha is overexpressed in AD brains, we investigated possible alterations of the cytokine-dependent pathway in PDAPP mice, a transgenic model of AD. Glutamate release was measured in acute hippocampal and cerebellar slices from mice at early (4-month-old) and late (12-month-old) disease stages in comparison with age-matched controls. Surprisingly, TNFalpha-evoked glutamate release, normal in 4-month-old PDAPP mice, was dramatically reduced in the hippocampus of 12-month-old animals. This defect correlated with the presence of numerous beta-amyloid deposits and hypertrophic astrocytes. In contrast, release was normal in cerebellum, a region devoid of beta-amyloid deposition and astrocytosis. The Ca2+-dependent process by which TNFalpha evokes glutamate release in acute slices is distinct from synaptic release and displays properties identical to those observed in cultured astrocytes, notably PG dependence. However, prostaglandin E2 induced normal glutamate release responses in 12-month-old PDAPP mice, suggesting that the pathology-associated defect involves the TNFalpha-dependent control of secretion rather than the secretory process itself. Reduced expression of DENN/MADD, a mediator of TNFalpha-PG coupling, might account for the defect. Alteration of this neuromodulatory astrocytic pathway is described here for the first time in relation to Alzheimer disease.

Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury

Traumatic brain injury (TBI) is a common cause of cognitive dysfunction and a major risk factor for Alzheimer’s disease (AD). PDAPP mice, a transgenic line overexpressing a mutant human amyloid precursor protein (APP) implicated in familial AD, have markedly impaired behavioral performance in the Morris water maze relative to wild-type (WT) littermates. Performance further deteriorates following experimental TBI in both PDAPP and WT mice. However, the aspects of cognitive function involved are not well understood. Here, we have analyzed search strategies used in the water maze by 3–4 month old PDAPP and WT C57Bl6 littermates both before and after moderate controlled cortical impact TBI. Prior to TBI, PDAPP mice used less spatial strategies and more nonspatial systematic strategies and strategies involving repetitive looping than WT mice. With training, PDAPP mice used more spatial strategies and less repetitive looping. After TBI, PDAPP mice lost use of spatial strategies and relied more on repetitive looping. TBI in WT mice also reduced their use of spatial strategies but instead caused a switch to nonspatial systematic strategies. We also analyzed changes in the efficiency with which mice used each individual strategy, but found that differences in which strategies were used quantitatively accounted for most of the differences in performance between groups. These results demonstrate that suboptimal search strategy use in addition to effects on spatial learning and memory underlies the impaired performance of PDAPP mice and further deterioration following TBI. Human TBI patients may have analogous poor use of problem solving strategies.

The PDAPP mouse model of Alzheimer's disease: Locus coeruleus neuronal shrinkage

Alzheimer's disease is characterized by neuronal degeneration in the cerebral cortex and hippocampus and subcortical neuronal degeneration in such nuclei as the locus coeruleus (LC). Transgenic mice overexpressing mutant human amyloid precursor protein V717F, PDAPP mice, develop several Alzheimer's disease-like lesions. The present study sought to determine whether there is also loss of LC noradrenergic neurons or evidence of degenerative changes in these animals. PDAPP hemizygous and wild-type littermate control mice were examined at 23 months of age, at a time when there are numerous amyloid-beta (Abeta) plaques in the neocortex and hippocampus. Tissue sections were stained immunohistochemically with an antibody against tyrosine hydroxylase (TH) to identify LC neurons. Computer imaging procedures were used to count the TH-immunoreactive somata in sections through the rostral-caudal extent of the nucleus. There was no loss of LC neurons in the hemizygous mice. In a second experiment, homozygous PDAPP and wild-type mice were examined, at 2 months and 24 months of age. Again there was no age-related loss of neurons in the homozygous animals. In the portion of the LC where neurons reside that project to the cortex and hippocampus, however, the neurons were decreased in size selectively in the 24-month-old transgenic animals. These data indicate that overt LC cell loss does not occur following abundant overexpression of Abeta peptide. However, the selective size reduction of the LC neuronal population projecting to cortical and hippocampal regions containing Abeta-related neuropathology implies that these cells may be subjected to a retrograde-mediated stress.