PDAPP Transgenic Mice Research Articles

Female dominance of both spatial cognitive dysfunction and neuropsychiatric symptoms in a mouse model of Alzheimer's disease.

Alzheimer’s disease (AD) is a prevalent neurological disorder affecting memory function in elderly persons. Indeed, AD exhibits abnormality in cognitive behaviors and higher susceptibility to neuropsychiatric symptoms (NPS). Various factors including aging, sex difference and NPS severity, are implicated during in development of AD. In this study, we evaluated behavioral abnormalities of AD model, PDAPP transgenic mice at young age using the Morris Water Maze test, which was established to assess hippocampal-dependent learning and memory. We found that female AD model mice exhibited spatial learning dysfunction and highly susceptible to NPS such as anxiety and depression, whereas spatial reference memory function was comparable in female PDAPP Tg mice to female wild type (WT) mice. Spatial learning function was comparable in male AD model mice to male WT mice. Multiple regression analysis showed that spatial learning dysfunction was associated with NPS severity such as anxiety and depression. Furthermore, the analysis showed that spatial reference memory function was associated with status of depression, but not anxiety. Thus, these results suggest female dominance of spatial learning dysfunction in the AD model mice accompanying increased NPS severity. The understandings of AD model may be useful for the development of therapeutic agents and methods in human AD.

Altered clearance of beta-amyloid from the cerebrospinal fluid following subchronic lead exposure in rats: Roles of RAGE and LRP1 in the choroid plexus

Formation of amyloid plaques is the hallmark of Alzheimer’s disease. Our early studies show that lead (Pb) exposure in PDAPP transgenic mice increases β-amyloid (Aβ) levels in the cerebrospinal fluid (CSF) and hippocampus, leading to the formation of amyloid plaques in mouse brain. Aβ in the CSF is regulated by the blood-CSF barrier (BCB) in the choroid plexus. However, the questions as to whether and how Pb exposure affected the influx and efflux of Aβ in BCB remained unknown. This study was conducted to investigate whether Pb exposure altered the Aβ efflux in the choroid plexus from the CSF to blood, and how Pb may affect the expression and subcellular translocation of two major Aβ transporters, i.e., the receptor for advanced glycation end-products (RAGE) and the low density lipoprotein receptor protein-1 (LRP1) in the choroid plexus. Sprague-Dawley rats received daily oral gavage at doses of 0, 14 (low-dose), and 27 (high-dose) mg Pb/kg as Pb acetate, 5 d/wk, for 4 or 8 wks. At the end of Pb exposure, a solution containing Aβ40 (2.5 μg/mL) was infused to rat brain via a cannulated internal carotid artery. Subchronic Pb exposure at both dose levels significantly increased Aβ levels in the CSF and choroid plexus (p < 0.05) by ELISA. Confocal data showed that 4-wk Pb exposures prompted subcellular translocation of RAGE from the choroidal cytoplasm toward apical microvilli. Furthermore, it increased the RAGE expression in the choroid plexus by 34.1 % and 25.1 % over the controls (p < 0.05) in the low- and high- dose groups, respectfully. Subchronic Pb exposure did not significantly affect the expression of LRP1; yet the high-dose group showed LRP1 concentrated along the basal lamina. The data from the ventriculo-cisternal perfusion revealed a significantly decreased efflux of Aβ40 from the CSF to blood via the blood-CSF barrier. Incubation of freshly dissected plexus tissues with Pb in artificial CSF supported a Pb effect on increased RAGE expression. Taken together, these data suggest that Pb accumulation in the choroid plexus after subchronic exposure reduces the clearance of Aβ from the CSF to blood by the choroid plexus, which, in turn, leads to an increase of Aβ in the CSF. Interaction of Pb with RAGE and LRP1 in choroidal epithelial cells may contribute to the altered Aβ transport by the blood-CSF barrier in brain ventricles.

COMBINATION THERAPY WITH A PLAQUE-SPECIFIC ABETA ANTIBODY AND A BACE INHIBITOR RESULTS IN DRAMATIC PLAQUE REDUCTION IN A DOSE-DEPENDENT MANNER IN AGED PDAPP TRANSGENIC MICE

COMBINATION THERAPY WITH A PLAQUE-SPECIFIC ABETA ANTIBODY AND A BACE INHIBITOR RESULTS IN DRAMATIC PLAQUE REDUCTION IN A DOSE-DEPENDENT MANNER IN AGED PDAPP TRANSGENIC MICE

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:

Paradoxical Effect of TrkA Inhibition in Alzheimer's Disease Models

An unbiased screen for compounds that block amyloid-β protein precursor (AβPP) caspase cleavage identified ADDN-1351, which reduced AβPP-C31 by 90%. Target identification studies showed that ADDN-1351 is a TrkA inhibitor, and, in complementary studies, TrkA overexpression increased AβPP-C31 and cell death. TrkA was shown to interact with AβPP and suppress AβPP-mediated transcriptional activation. Moreover, treatment of PDAPP transgenic mice with the known TrkA inhibitor GW441756 increased sAβPPα and the sAβPPα to Aβ ratio. These results suggest TrkA inhibition-rather than NGF activation-as a novel therapeutic approach, and raise the possibility that such an approach may counteract the hyperactive signaling resulting from the accumulation of active NGF-TrkA complexes due to reduced retrograde transport. The results also suggest that one component of an optimal therapy for Alzheimer's disease may be a TrkA inhibitor.

Hormonal modulators of glial ABCA1 and apoE levels

Apolipoprotein E (apoE) is the major lipid carrier in the central nervous system. As apoE plays a major role in the pathogenesis of Alzheimer disease (AD) and also mediates repair pathways after several forms of acute brain injury, modulating the expression, secretion, or function of apoE may provide potential therapeutic approaches for several neurological disorders. Here we show that progesterone and a synthetic progestin, lynestrenol, significantly induce apoE secretion from human CCF-STTG1 astrocytoma cells, whereas estrogens and the progesterone metabolite allopregnanolone have negligible effects. Intriguingly, lynestrenol also increases expression of the cholesterol transporter ABCA1 in CCF-STTG1 astrocytoma cells, primary murine glia, and immortalized murine astrocytes that express human apoE3. The progesterone receptor inhibitor RU486 attenuates the effect of progestins on apoE expression in CCF-STTG1 astrocytoma cells but has no effect on ABCA1 expression in all glial cell models tested, suggesting that the progesterone receptor (PR) may participate in apoE but does not affect ABCA1 regulation. These results suggest that selective reproductive steroid hormones have the potential to influence glial lipid homeostasis through liver X receptor-dependent and progesterone receptor-dependent pathways.

P2‐390: Emerging relationship between development and degeneration: TrkA‐APP interaction as a therapeutic target in Alzheimer's disease

It has been proposed that disrupted retrograde transport of NGF-TrkA complexes underlies basal forebrain cholinergic neuron (BFCN) degeneration in Alzheimer's disease (AD). Indeed, targeted BFCN delivery of NGF has been found promising in AD treatment and is currently in a phase II clinical trial. The prevailing view of Alzheimer's disease (AD) is that amyloid-beta (Abeta) causes toxicity through chemical and physical mechanisms. Our data suggest that Abeta functions physiologically as an anti-trophin, and Abeta binding to APP induces APP processing to multiple peptides that mediate physiological neurite retraction and synaptic reorganization (Nat Med 6:397; PNAS 103:7130). An unbiased screen for compounds that block APP caspase cleavage identified ADDN1351, which reduced APP-C31 by 90%. Surprisingly, ADDN1351 proved to be a TrkA inhibitor. We then evaluated the effect of TrkA over-expression on APP-C31 production and cell death induction through transfection, Western blots and MTT assays. We also studied the interaction between APP and TrkA through co-immunoprecipitation and APP-Gal4 transactivation. Furthermore, we treated PDAPP transgenic mice with TrkA inhibitor GW441756 (10mg/kg, 5 days) and assayed the levels of Abeta and sAPPalpha through ELISA and AlphaLISA. TrkA over-expression increased APP-C31 and cell death. APP-C31 cleavage did not occur with the kinase-dead TrkA mutant or in the presence of TrkA inhibitor GW441756, whereas induction was enhanced by NGF. TrkA was shown to interact with APP in co-immunoprecipitation. In APP-Gal4 transactivation assays, TrkA inhibited the transactivation directed by Fe65 or Mint3/YAP by over 90%. Moreover, treatment of PDAPP transgenic mice with GW441756 not only decreased Abeta, but also increased sAPPalpha. These results suggest TrkA inhibition-rather than NGF activation-as a novel therapeutic approach, and raise the possibility that such an approach may counteract the hyperactive signaling resulting from the accumulation of active NGF-TrkA complexes due to reduced retrograde transport. The results also suggest that the optimal therapy for AD may involve both the delivery of NGF or NGF mimetics to basal forebrain cholinergic neuron somata and a TrkA inhibitor that is active more distally.

The “Brain–Skin Connection” in Protein Misfolding and Amyloid Deposits: Embryological, Pathophysiological, and Therapeutic Common Grounds?

A brief history of amyloidosis goes back to autopsies of the seventeenth century reporting a waxing substance (Cordier, 2008). Later, in the middle of the nineteenth century, Rudolph Virchow described an “amyloid” (starch, amulon, Greek, amylum, Latin) degeneration and infiltration of the lungs within alveoli and small vessels in a patient who presented with systemic amyloidosis (heart, lungs, liver, and kidneys; Cordier, 2008). What amyloid-related diseases share is a common molecular ternary structure which involves abnormal aggregation of numerous widespread copies of the same protein into well-ordered filamentous β-sheet rich structures (Friedman, 2011) known as amyloid fibrils of 10–12 nm diameters (Plante-Bordeneuve and Said, 2011). This abnormal accumulation of amyloid oligomers, protofibrils, or fibrils is considered to be one of the major contributor to neurodegeneration and the hallmark of Alzheimer's (AD) and Parkinson's diseases (Arora et al., 2004). A primary cause underlying these accumulations is the folding of polypeptide chains to specific three-dimensional proteins in abnormal ways (Selkoe, 2003). The progressive misfolding of specific proteins into aggregation may lead to cell alteration or death. Aggregated forms share many characteristics. One of them is that amyloid deposits show specific optical behavior such as birefringence on binding dyes (Congo red). The systemic distribution of amyloidoses may produce extracellular deposits in multiple organs (Joachim et al., 1989). In this paper, Clos, Kayed, and Lasagna-Reeves present a novel perspective about the relation of dermis–epidermis–brain and offer a review about amyloid deposits that are central to the strong “brain–skin” connection. This connection starts as early as the sharing a joint embryological origin. Common multipotent embryonic progenitor stem cells from the ectoderm on the surface of the post-gastrulation embryo receive specific signaling from their environment that instruct them to commit to a particular differentiation program which will give rise to the nervous system or skin epithelium (Quan and Hassan, 2005; Fuchs, 2007). Clos, Kayed, and Lasagna-Reeves highlight common “brain–skin” pathophysiological disorders such as the role of presenilin 1 (PS-1) for proteolytic processing of the amyloid precursor protein (APP) which is altered in AD; alteration also found in skin cancers (Xia et al., 2001; Kang et al., 2002). They also draw parallels between neurodegenerative disorders of Parkinson's disease (Lewy bodies, α-synuclein, melanin) and amyotrophic lateral sclerosis (ALS inclusion bodies) which share common features with skin diseases (Hays et al., 2006). In addition, Clos, Kayed, and Lasagna-Reeves are describing transdermal route-of-entry as an elected administration route for potential medications to patients with neurodegenerative diseases such as Rivastigmine (AD and Parkinson), Rotigotine (Parkinson). A favorable coefficient of partition (physiologically based pharmacokinetics, PBPK; Thrall et al., 2002) to the brain via the skin vector seems promising for potential drugs targeting the brain (Zhao et al., 2011). In PDAPP transgenic mice, the immunization with the 42-amino-acid form of the peptide (Aβ42) prevents the development of cerebral β-amyloid-plaque formation, neuritic dystrophy and astrogliosis (Schenk et al., 1999); the transdermal route has also been successfully used without detrimental side effects such as T cell infiltration and cerebral microhemorrhage (Nikolic et al., 2007). Occurrence of the systemic deposition of β-amyloid protein in multiple tissues such as skin or brain infers that the initial amyloid protein may be produced locally in all organs affected or may, as observed in other human amyloidoses, be derived from a common circulating precursor (Joachim et al., 1989). Therefore the transdermal β-amyloid immunization also directly targeting skin β-amyloid deposits may further reduce a potential source for amyloid precursors to other organs such as the brain.

Lipoprotein Lipase Is a Novel Amyloid β (Aβ)-binding Protein That Promotes Glycosaminoglycan-dependent Cellular Uptake of Aβ in Astrocytes

Lipoprotein lipase (LPL) is a member of a lipase family known to hydrolyze triglyceride molecules in plasma lipoprotein particles. LPL also plays a role in the binding of lipoprotein particles to cell-surface molecules, including sulfated glycosaminoglycans (GAGs). LPL is predominantly expressed in adipose and muscle but is also highly expressed in the brain where its specific roles are unknown. It has been shown that LPL is colocalized with senile plaques in Alzheimer disease (AD) brains, and its mutations are associated with the severity of AD pathophysiological features. In this study, we identified a novel function of LPL; that is, LPL binds to amyloid β protein (Aβ) and promotes cell-surface association and uptake of Aβ in mouse primary astrocytes. The internalized Aβ was degraded within 12 h, mainly in a lysosomal pathway. We also found that sulfated GAGs were involved in the LPL-mediated cellular uptake of Aβ. Apolipoprotein E was dispensable in the LPL-mediated uptake of Aβ. Our findings indicate that LPL is a novel Aβ-binding protein promoting cellular uptake and subsequent degradation of Aβ.

Traumatic brain injury reduces soluble extracellular amyloid-β in mice: A methodologically novel combined microdialysis-controlled cortical impact study

Acute amyloid-β peptide (Aβ) deposition has been observed in young traumatic brain injury (TBI) patients, leading to the hypothesis that elevated extracellular Aβ levels could underlie the increased risk of dementia following TBI. However, a recent microdialysis-based study in human brain injury patients found that extracellular Aβ dynamics correlate with changes in neurological status. Because neurological status is generally diminished following injury, this correlation suggested the alternative hypothesis that soluble extracellular Aβ levels may instead be reduced after TBI relative to baseline. We have developed a methodologically novel mouse model that combines experimental controlled cortical impact TBI with intracerebral microdialysis. In this model, we found that Aβ levels in microdialysates were immediately decreased by 25–50% in the ipsilateral hippocampus following TBI. This result was found in PDAPP, Tg2576, and Tg2576-ApoE2 transgenic mice producing human Aβ plus wild-type animals. Changes were not due to altered probe function, edema, changes in APP levels, or Aβ deposition. Similar decreases in Aβ were observed in phosphate buffered saline-soluble tissue extracts. Hippocampal electroencephalographic activity was also decreased up to 40% following TBI, and correlated with reduced microdialysate Aβ levels. These results support the alternative hypothesis that post-injury extracellular soluble Aβ levels are acutely decreased relative to baseline. Reduced neuronal activity may contribute, though the underlying mechanisms have not been definitively determined. Further work will be needed to assess the dynamics of insoluble and oligomeric Aβ after TBI.

Proof-of-concept pharmacodynamic assessment of a prototypic BACE1 inhibitor at steady-state using IV infusion dosing in the PDAPP transgenic mouse model of Alzheimer's disease

Proof-of-concept pharmacodynamic assessment of a prototypic BACE1 inhibitor at steady-state using IV infusion dosing in the PDAPP transgenic mouse model of Alzheimer's disease

Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease

BackgroundReduced TOR signaling has been shown to significantly increase lifespan in a variety of organisms [1], [2], [3], [4]. It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target p70S6K[6] extends lifespan in mice, possibly by delaying aging. Whether inhibition of the mTOR pathway would delay or prevent age-associated disease such as AD remained to be determined.Methodology/Principal FindingsWe used rapamycin administration and behavioral tools in a mouse model of AD as well as standard biochemical and immunohistochemical measures in brain tissue to provide answers for this question. Here we show that long-term inhibition of mTOR by rapamycin prevented AD-like cognitive deficits and lowered levels of Aβ42, a major toxic species in AD[7], in the PDAPP transgenic mouse model. These data indicate that inhibition of the mTOR pathway can reduce Aβ42 levels in vivo and block or delay AD in mice. As expected from the inhibition of mTOR, autophagy was increased in neurons of rapamycin-treated transgenic, but not in non-transgenic, PDAPP mice, suggesting that the reduction in Aβ and the improvement in cognitive function are due in part to increased autophagy, possibly as a response to high levels of Aβ.Conclusions/SignificanceOur data suggest that inhibition of mTOR by rapamycin, an intervention that extends lifespan in mice, can slow or block AD progression in a transgenic mouse model of the disease. Rapamycin, already used in clinical settings, may be a potentially effective therapeutic agent for the treatment of AD.

Tg-SwDI Transgenic Mice Exhibit Novel Alterations in AβPP Processing, Aβ Degradation, and Resilient Amyloid Angiopathy

Alzheimer's disease (AD) is characterized by the accumulation of extracellular insoluble amyloid, primarily derived from polymerized amyloid-beta (Abeta) peptides. We characterized the chemical composition of the Abeta peptides deposited in the brain parenchyma and cerebrovascular walls of triple transgenic Tg-SwDI mice that produce a rapid and profuse Abeta accumulation. The processing of the N- and C-terminal regions of mutant AbetaPP differs substantially from humans because the brain parenchyma accumulates numerous, diffuse, nonfibrillar plaques, whereas the thalamic microvessels harbor overwhelming amounts of compact, fibrillar, thioflavine-S- and apolipoprotein E-positive amyloid deposits. The abundant accretion of vascular amyloid, despite low AbetaPP transgene expression levels, suggests that inefficient Abeta proteolysis because of conformational changes and dimerization may be key pathogenic factors in this animal model. The disruption of amyloid plaque cores by immunotherapy is accompanied by increased perivascular deposition in both humans and transgenic mice. This analogous susceptibility and response to the disruption of amyloid deposits suggests that Tg-SwDI mice provide an excellent model in which to study the functional aftermath of immunotherapeutic interventions. These mice might also reveal new avenues to promote amyloidogenic AbetaPP processing and fundamental insights into the faulty degradation and clearance of Abeta in AD, pivotal issues in understanding AD pathophysiology and the assessment of new therapeutic agents.

O3-01-06: Evidence of vascular recovery after removal of vascular Aβ by passive immunotherapy in PDAPP mice

Background: Cerebral amyloid angiopathy is a common neuropathological feature of Alzheimer’s disease and is characterized by vascular deposition of fibrillar amyloid -protein (VA ). Vascular structural changes are associated with VA deposits, including localized loss of smooth muscle cells (SMC) and changes in extracellular matrix (ECM). Passive immunization with antibodies to the A N-terminus (3D6, aa 1-5) has been shown to effectively reduce amyloid deposition in the vasculature of PDAPP transgenic mice. In the present study we characterized structural changes induced by amyloid on SMC and ECM of PDAPP mouse vessels and assessed the effects of passive immunotherapy. Methods: Mice were immunized weekly for either 3 or 9 months with 1 or 3 mg/Kg of 3D6 antibody. High-resolution, quantitative IHC analyses of vascular components ( -actin for SMC and collagen-IV for ECM) were performed on meningeal vessels from the sagittal sinus, where VA deposition is prominent ( 70% of vessels affected). Microhemorrhage events were monitored by hemosiderin detection or ferritin immunohistochemistry. Results: We found that changes in the vascular wall are invariably associated with VA , and they included both degeneration (decreased thickness) and hyperplasia/hypertrophy (increased thickness) of SMC and ECM. These two contrasting findings were often observed in the same vessel and were not present in wild type animals or PDAPP vessels lacking amyloid. The extreme degrees of thickening and thinning of the SM resulted in a widely variable vascular phenotype in untreated PDAPP mice. Passive immunotherapy restored the pattern of vascular SMC and ECM thicknesses and reduced the phenotypic variability in a doseand time-dependent manner, with the high dose of 3D6 reaching control levels (wild type) at 9 months. Although the incidence of microhemorrhage increased in the 3-month group, it reduced to control levels after 9 months of treatment. Conclusions: Our results suggest that passive immunotherapy allows the recovery of meningeal vessels from amyloid-induced structural changes. Furthermore, the treatment-related increase in microhemorrhage appears to be a transient event that resolves during VA clearance. Mechanisms of repair may be triggered by VA removal, which ultimately lead to recovery from vascular dysfunction. Experiments to assess this possibility are in progress.

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.

Neuropathological changes in the PDAPP transgenic mouse model of Alzheimers disease

Neuropathological changes in the PDAPP transgenic mouse model of Alzheimers disease

Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities

Dystrophic neurites are swollen dendrites or axons recognizable near amyloid plaques as a part of important pathological feature of Alzheimer's disease (AD). We report herein that reticulon 3 (RTN3) is accumulated in a distinct population of dystrophic neurites named as RTN3 immunoreactive dystrophic neurites (RIDNs). The occurrence of RIDNs is concomitant with the formation of high-molecular-weight RTN3 aggregates in brains of AD cases and mice expressing mutant APP. Ultrastructural analysis confirms accumulation of RTN3-containing aggregates in RIDNs. It appears that the protein level of RTN3 governs the formation of RIDNs because transgenic mice expressing RTN3 will develop RIDNs, initially in the hippocampal CA1 region, and later in other hippocampal and cortical regions. Importantly, we show that the presence of dystrophic neurites in Tg-RTN3 mice causes impairments in spatial learning and memory, as well as synaptic plasticity, implying that RIDNs potentially contribute to AD cognitive dysfunction. Together, we demonstrate that aggregation of RTN3 contributes to AD pathogenesis by inducing neuritic dystrophy. Inhibition of RTN3 aggregation is likely a therapeutic approach for reducing neuritic dystrophy.

Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid-β peptide levels in vivo

ABCA1-deficient mice have low levels of poorly lipidated apolipoprotein E (apoE) and exhibit increased amyloid load. To test whether excess ABCA1 protects from amyloid deposition, we crossed APP/PS1 mice to ABCA1 bacterial artificial chromosome (BAC) transgenic mice. Compared with wild-type animals, the ABCA1 BAC led to a 50% increase in cortical ABCA1 protein and a 15% increase in apoE abundance, demonstrating that this BAC supports modest ABCA1 overexpression in brain. However, this was observed only in animals that do not deposit amyloid. Comparison of ABCA1/APP/PS1 mice with APP/PS1 controls revealed no differences in levels of brain ABCA1 protein, amyloid, Abeta, or apoE, despite clear retention of ABCA1 overexpression in the livers of these animals. To further investigate ABCA1 expression in the amyloid-containing brain, we then compared ABCA1 mRNA and protein levels in young and aged cortex and cerebellum of APP/PS1 and ABCA1/APP/PS1 animals. Compared with APP/PS1 controls, aged ABCA1/APP/PS1 mice exhibited increased ABCA1 mRNA, but not protein, selectively in cortex. Additionally, ABCA1 mRNA levels were not increased before amyloid deposition but were induced only in the presence of extensive Abeta and amyloid levels. These data suggest that an induction of ABCA1 expression may be associated with late-stage Alzheimer's neuropathology.

Anti-Aβ antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice

Anti-Aβ antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice

P1-003: Thiorphan infusion induces deposition of beta-amyloid in PDAPP transgenic mice

P1-003: Thiorphan infusion induces deposition of beta-amyloid in PDAPP transgenic mice