Aβ Deposition In Brain Research Articles

Association between promoter polymorphisms in anterior pharynx-defective-1a and sporadic Alzheimer's disease in the North Chinese Han population

Amyloid β-peptide (Aβ) deposition in brain is important in the development of sporadic Alzheimer's disease (SAD) and Aβ is produced through sequential cleaving of amyloid precursor protein (APP) by β-secretase and γ-secrease. Anterior pharynx-defective-1 (APH-1) is an important subunit of the gamma-secretase complex, and its expression level was associated with the activity of γ-secrease. We hypothesized that alterations in the APH-1 promoter region might alter APH-1 expression and the activity of γ-secrease, thus be involved in the SAD process. In the present study, we sequenced APH-1a promoter region in 20 randomly selected controls and 20 SAD patients and detected two polymorphisms which were −980C/G (rs3754048) and −21C/A (rs2275780). Then, we investigated genotypes and allele of these two polymorphisms as well as apolipoprotein ɛ4 (APOE ɛ4) status in 256 SAD patients and 276 normal controls with restriction fragment length polymorphisms analysis and sequencing. Results showed the GG genotype and G allele of −980C/G polymorphism were more frequent in the SAD group than that in the controls not only in the whole subjects (genotype P = 0.038, allele P = 0.01 respectively) but also in the APOE ɛ4 + subjects (genotype P = 0.048, allele P = 0.016 respectively). There was no statistical difference between SAD group and controls regarding to the frequency of alleles and genotypes of −21C/A whenever before or after stratification by APOE ɛ4. Our results suggest that there is an association between −980C/G and the development of SAD in the Northern Han Chinese population and that allele G may interact synergistically with the APOE ɛ4 allele to increase the risk of SAD.

11C]PIB-amyloid binding and levels of Aβ40 and Aβ42 in postmortem brain tissue from Alzheimer patients

β-Amyloid (Aβ) deposits are one of the major histopathological hallmarks of Alzheimer's disease (AD). The amyloid-imaging positron emission tomography (PET) tracer [ 11C]PIB ( N-methyl[ 11C]2-(4′-methylaminophenyl)-6-hydroxy-benzothiazole) is used in the assessment of Aβ deposits in the human brain. [ 11C]PIB-amyloid interaction and insoluble Aβ40 and Aβ42 peptide levels in the brain were quantified in postmortem tissue from nine AD patients and nine age-matched control subjects in the temporal, frontal and parietal cortices and the cerebellum. Autoradiographical studies showed significantly higher densities of specific [ 11C]PIB-amyloid binding in gray matter in the temporal and parietal cortex (62 fmol/mg tissue) in AD patients as compared to control subjects, whereas the density was somewhat lower in the frontal cortex (56 fmol/mg tissue). No specific binding could be detected in the AD cerebellum or in the tissues from the control subjects (≤5 fmol/mg tissue). Insoluble Aβ40 and total Aβ levels (i.e. sum of Aβ40 and Aβ42) were significantly higher in patients than in controls in all measured cortical regions as determined using ELISA, which was confirmed using immunohistochemistry. The present findings show a more regional selective distribution of [ 11C]PIB amyloid binding than previously reported. Moreover, it is suggested that some of the [ 11C]PIB binding and insoluble Aβ seen in control subjects may be amyloid in the blood vessels.

Exceptional Amyloid β Peptide Hydrolyzing Activity of Nonphysiological Immunoglobulin Variable Domain Scaffolds

Nucleophilic sites in the paired variable domains of the light and heavy chains (VL and VH domains) of Ig can catalyze peptide bond hydrolysis. Amyloid beta (Abeta)-binding Igs are under consideration for immunotherapy of Alzheimer disease. We searched for Abeta-hydrolyzing human IgV domains (IgVs) in a library containing a majority of single chain Fv clones mimicking physiological VL-VH-combining sites and minority IgV populations with nonphysiological structures generated by cloning errors. Random screening and covalent selection of phage-displayed IgVs with an electrophilic Abeta analog identified rare IgVs that hydrolyzed Abeta mainly at His14-Gln15. Inhibition of IgV catalysis and irreversible binding by an electrophilic hapten suggested a nucleophilic catalytic mechanism. Structural analysis indicated that the catalytic IgVs are nonphysiological structures, a two domain heterodimeric VL (IgVL2-t) and single domain VL clones with aberrant polypeptide tags (IgVL-t'). The IgVs hydrolyzed Abeta at rates superior to naturally occurring Igs by 3-4 orders of magnitude. Forced pairing of the single domain VL with VH or VL domains resulted in reduced Abeta hydrolysis, suggesting catalysis by the unpaired VL domain.Angstrom level amino acid displacements evident in molecular models of the two domain and unpaired VL domain clones explain alterations of catalytic activity. In view of their superior catalytic activity, the VL domain IgVs may help attain clearance of medically important antigens more efficiently than natural Igs.

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to beta-amyloid (Abeta) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain Abeta deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.

Increased oxidative stress and astrogliosis responses in conditional double-knockout mice of Alzheimer-like presenilin-1 and presenilin-2

Conditional presenilin 1 and presenilin 2 double knockout causes memory dysfunction and reproduces neurodegenerative phenotypes of Alzheimer disease (AD) in mice. Oxidative stress has been long implicated predominantly in amyloidosis-mediated AD pathologies; however, its role in response to the loss-of-function pathogenic mechanism of AD remains unclear. In this study, we examined the oxidative stress status in PS1 and PS2 double-knockout (PS cDKO) mice using F 2-isoprostanes (iPF 2α-III) as the marker of lipid peroxidation. Lipid peroxidation was enhanced in a gender- and age-related manner in the PS cDKO mice independent of brain Aβ deposition. Such oxidative abnormalities predominantly in cerebral cortex at 2–4 months of age preceded the onset of many pronounced AD neuropathologies, suggesting that increased lipid peroxidation is not only an early pathophysiological response to PS inactivation, but also a potential culprit responsible for the AD-like neurodegenerative pathologies in the PS cDKO mice. Western blot analysis of cortical glial fibrillary acidic protein demonstrated an increased astrogliosis response to PS inactivation, in particular in the PS cDKO mice at as young as 2 months of age, suggesting that lipid peroxidation and neuronal injury may be closely associated with the loss-of-function neuropathogenic mechanism of AD.

P4-029: Herpes simplex virus type 1 (HSV1) in brain: A cause of the neuropathological features of Alzheimer's disease?

The causes of AD remain unknown, despite extensive studies on amyloid plaques and neurofibrillary tangles. We have implicated the virus, HSV1, as a major factor. We discovered that latent HSV1 is present in a high proportion of elderly brains (Jamieson et al., 1991), and in carriers of the type 4 allele of the apolipoprotein E gene (APOE-e4) it confers a strong risk of AD (Itzhaki et al., 1997); also, it reactivates from latency in brain, causing an acute infection – possibly recurrently (Wozniak et al., 2005). Immunocytochemistry; ELISA; Western blotting; in situ PCR. We have linked HSV1 directly to AD brain abnormalities: (1) HSV1 infection of cultured cells causes intracellular deposition of Aβ (Wozniak et al., 2007); (2) HSV1 infection of mice results in Aβ deposition in brain (Wozniak et al., 2007); (3) HSV1 infection of cultured cells causes AD-like phosphorylation of tau (Wozniak et al., to be submitted). These changes result from increases in the relevant secretases and kinases, and are likely due to HSV1 subverting cell processes to aid its replication, taking over the protein-synthesising machinery, and causing entry into cycle, although as in AD, only up to G2/M. As for the role of APOE-e4 with HSV1 in AD, we propose that it determines extent of HSV1 damage. This is strongly supported by our discovery that APOE determines outcome of infection in several diseases of known microbial cause (Wozniak & Itzhaki, 2006). Further, on examining HSV1 location in relation to amyloid plaques in AD brain, we found 90% of plaques associated with viral DNA and most of the viral DNA is located in plaques (Wozniak et al., submitted). This co-localisation, together with our discovery that HSV1 induces amyloid deposition, strongly implicates HSV1 in plaque formation and AD development (we can refute explanations that co-localisation results from plaque formation). Our data strongly implicate HSV1 as a major factor in AD. They support antiviral usage to prevent deterioration of patients and possibly in future, vaccination against HSV1 (which protects against establishment of viral latency in mouse brain – Lin et al., 2001) to prevent AD occurrence.

Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition

There is substantial evidence that cerebrospinal fluid (CSF) levels of both Abeta42 and tau/ptau are promising biomarkers for Alzheimer's disease (AD). We show that both Abeta and tau exhibit more than 10-fold interindividual variation in CSF levels suggesting that these biomarkers may also be effectively used as endophenotypes for genetic studies of AD. To test the role of common variation in the gene encoding microtubule associated protein tau (MAPT) in influencing CSF tau/ptau levels, we genotyped 21 MAPT single nucleotide polymorphisms (SNPs) in 313 individuals and tested for association with CSF tau/ptau levels. We identified alleles of several SNPs that show association with increased CSF tau/ptau levels. When CSF Abeta42 levels were used to stratify the sample into those with and without likely Abeta deposition in the brain the association was only observed in individuals with evidence of Abeta deposition. This association was replicated in an independent CSF series. When these SNPs were evaluated in a late-onset AD case control series the alleles associated with higher CSF tau/ptau were associated with an earlier age at onset but had no effect on risk for AD. In vivo gene expression studies show that these alleles are associated with increased MAPT mRNA levels in individuals with evidence of brain Abeta deposition. This endophenotype-based approach provides evidence for a gene (MAPT SNPs)-physiological environment (Abeta deposition) interaction that places changes in CSF tau after Abeta deposition and suggest that this interaction predisposes for the development of tauopathy and accelerated disease progression.

Standard versus patient-centred asthma education in the emergency department: a randomised study

High re-attendance rates are common after asthma emergency department (ED) care. Inadequate patient education has been cited as a potential cause of re-attendance and the optimal format of education is uncertain. The present study aimed to compare the effectiveness of patient-centred education (PCE) and standard asthma patient education on ED re-attendance. A randomised controlled trial was conducted at two inner-city Australian teaching hospitals' EDs, where patients received either standard patient education (SPE) or PCE. Both groups received a six-topic curriculum. However, PCE patients reordered the topics according to their own priority and thus controlled the order of education. In total, 146 adult patients presenting to EDs with acute asthma were enrolled. After 4 months, ED re-attendance decreased from 22 to 12% in the PCE group and remained unchanged in the SPE group (between group odds ratio 0.4, 95% confidence interval (0.2-1.1)). In 78 patients discharged after ED care, the PCE group had fewer re-attendances after 4 and 12 months (0.3 (0.1-0.9) and 0.3 (0.1-0.8), respectively ). PCE patients with no general practitioner care in the preceding 7 days had fewer re-attendances after 4 and 12 months (0.1 (0.0-0.7) and 0.2 (0.0-0.6), respectively). A trend of better asthma control was evident, with a reduction in activity limitation. In conclusion, patient-centred education offers promise as a brief education process in the emergency department. However, a large multicentre trial of patient-centred education is required.

Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology

Down-regulation of protein phosphatase 2A (PP2A) is thought to play a critical role in tau hyperphosphorylation in Alzheimer's disease (AD). In vitro phosphorylation of PP2A catalytic subunit at Y307 efficiently inactivates PP2A. A specific antibody against phosphorylated (p) PP2A (Y307) (PP2Ac-Yp307) was used to investigate possible PP2A down-regulation by known pathophysiological changes associated with AD, such as Aβ accumulation and oestrogen deficiency. Immunohistochemistry and immunofluorescence confocal microscopy showed an aberrant accumulation of PP2Ac-Yp307 in neurons that bear pretangles or tangles in the susceptible brain regions, such as the entorhinal cortical cortex and the hippocampus. Experimentally, increased PP2Ac-Yp307 was observed in mouse N2a neuroblastoma cells that stably express the human amyloid precursor protein with Swedish mutation (APPswe) compared with wild-type, and in the brains of transgenic APPswe/ presenilin (PS1, A246E) mice, which corresponded to the increased tau phosphorylation. Treating N2a cells with Aβ25–35 mimicked the changes of PP2Ac-Yp307 and tau phosphorylation in N2a APPswe cells. Knockout of oestrogen receptor (ER) α or ERβ gave similar changes of PP2Ac-Yp307 level and tau phosphorylation in the mouse brain. Taken together, these findings suggest that increased PP2A phosphorylation (Y307) can be mediated by Aβ deposition or oestrogen deficiency in the AD brain, and consequently compromise dephosphorylation of abnormally hyperphosphorylated tau, and lead to neurofibrillary tangle formation.

Fermented papaya preparation attenuates β-amyloid precursor protein: β-amyloid–mediated copper neurotoxicity in β-amyloid precursor protein and β-amyloid precursor protein Swedish mutation overexpressing SH-SY5Y cells

Recent studies indicate that the deposition of β-amyloid (Aβ) is related in the pathogenesis of Alzheimer’s disease (AD), but the underlying mechanism is still not clear. The abnormal interactions of Aβ with metal ions such as copper are implicated in the process of Aβ deposition and oxidative stress in AD brains. In the present study, we established a new AD model, using which we found that copper triggered the Aβ neurotoxicity in SH-SY5Y cells overexpressing the Swedish mutant form of human APP (APPsw) in a concentration dependent manner. Fermented papaya preparation (FPP) has shown high free radical scavenging ability in vivo and in vitro. FPP post-treatment increased cell viability and decreased the intracellular [Ca 2+] i, reactive oxygen species (ROS) generation such as hydroxyl free radical and superoxide anion and nitric oxide (NO) accumulation in the cell. Our results also show that FPP prevents the cell apoptosis through bax/bcl-2 sensitive pathway.

P1-379: Heparan sulphate proteoglycans affect the biological activity of Aβ

Amyloid beta (Aβ) deposits in Alzheimer's disease brains, i.e. senile plaques and vascular amyloid, also contain heparan sulphate proteoglycans (HSPGs). HSPGs consist of a protein core with sulphated glycosaminoglycans (GAGs) attached. The expression of HSPG in plaques suggests that these proteins play a role in the deposition of Aβ. It has been suggested that HSPGs may affect Aβ aggregation and clearance. However, the spatiotemporal association between HSPGs and Aβ has not yet been studied. Similarly, it is not known how HSPG/GAG expression relates to Aβ expression and biological activity. 1) to study in vitro (in human brain pericytes) the expression of HSPGs in response to Aβ; 2) to study in vitro (in human brain pericytes and smooth muscle cells) the role of GAGs in Aβ–mediated cellular toxicity; 3) to investigate the spatiotemporal association of HSPGs with Aβ. Protein expression of HSPGs was determined using Western blot analysis. RNA expression was measured using a quantitative RT–PCR (Taqman). The effect of GAGs on Aβ–mediated cellular toxicity was investigated using viability assays. In vitro, protein expression of the HSPGs agrin and glypican–1 and the degree of glycosylation of these HSPGs in pericytes was upregulated after treatment with Aβ. To confirm these findings at the mRNA level, quantitative PCR was performed. Finally, we demonstrated that several GAGs dose–dependently inhibited Aβ–mediated cellular degeneration in pericytes and smooth muscle cells. Moreover, we observed that the degree of inhibition was dependent on the degree of sulphation of the GAGs. In conclusion, GAGs may modulate the biological activity of Aβ and this capacity is related to the degree of negatively charged sulphate groups present in these GAGs. Furthermore, HSPG expression (both at the protein level and degree of glycosylation) is increased in response to Aβ. This suggests that HSPG expression in senile plaques and vascular amyloid follows the expression of Aβ. Currently, a study to confirm this association between Aβ and HSPGs, by investigating the expression of HSPGs in relation to Aβ expression in transgenic mice (APPSwe/PS–1 and SwDI Tg mice) during different stages of lesion development, is in progress.

Cholesterol 25-Hydroxylase on Chromosome 10q Is a Susceptibility Gene for Sporadic Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia. It is characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5′ region of CH25H revealed three common haplotypes, CH25Hχ2, CH25Hχ3 and CH25Hχ4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hχ4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain Aβ deposits in carriers of CH25Hχ4 and CH25Hχ3 haplotypes, whereas no Aβ deposits were present in CH25Hχ2 carriers. Together, these results are compatible with a role of CH25Hχ4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain Aβ deposition.

Targeting Amyloid-β Peptide (Aβ) Oligomers by Passive Immunization with a Conformation-selective Monoclonal Antibody Improves Learning and Memory in Aβ Precursor Protein (APP) Transgenic Mice

Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid-beta peptide (Abeta) levels and improves cognitive function. To specifically address the role of Abeta oligomers in learning and memory, we generated a novel monoclonal antibody, NAB61, that preferentially recognizes a conformational epitope present in dimeric, small oligomeric, and higher order Abeta structures but not full-length amyloid-beta precursor protein or C-terminal amyloid-beta precursor protein fragments. NAB61 also recognized a subset of brain Abeta deposits, preferentially mature senile plaques, and amyloid angiopathy. Using NAB61 as immunotherapy, we showed that aged Tg2576 transgenic mice treated with NAB61 displayed significant improvements in spatial learning and memory relative to control mice. These data implicated Abeta oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.

Vessel ultrastructure in APP23 transgenic mice after passive anti-Aβ immunotherapy and subsequent intracerebral hemorrhage

Passive immunization of amyloid precursor protein (APP) transgenic mice with anti-amyloid beta (Aβ) antibodies was shown to reduce Aβ-deposition in brain and to improve cognition. However, immunotherapy may also be accompanied by a significant increase in the frequency of intracerebral hemorrhages. Because hemorrhages are associated with amyloid-laden vessels, this raises the question whether high concentrations of anti-Aβ antibodies may directly or indirectly lead to a structural destabilization of the vessel wall. To address this point, transmission electron microscopy was performed and the ultrastructure of bleeding and non-bleeding vessels in immunized and non-immunized APP23 transgenic animals was analyzed. To localize bleeding vessels, hemosiderin-positive macrophages were visualized by pre-embedding Perl's Berlin Blue histochemistry. Vessels were analyzed morphologically, anomalies evaluated and quantified. Bleeding vessels were, furthermore, reconstructed in three dimensions to analyze the spatial distribution of amyloid deposits and other pathological changes of the vessel wall. This in-depth morphological analysis revealed that bleeding vessels in immunized as well as in non-immunized APP23 mice were surrounded by a higher number of macrophages compared to non-bleeding vessels in the same animals. However, no differences in the number of macrophages or other structural parameters, such as amyloid deposition, were observed between bleeding vessels of immunized and non-immunized mice. No pathologies which may indicate impending bleeding were observed in the vascular wall of non-bleeding vessels. We conclude, that the increased hemorrhage frequency observed after passive immunization with anti-Aβ antibodies does not lead to overt structural changes in the vessel wall of APP23 transgenic mice. Minor structural alterations of the vessel wall, however, cannot be excluded due to the sample size of our study and the high complexity of the three-dimensional vessel wall ultrastructure.

Suppression of Aβ deposition in brain by peripheral administration of Fab fragments of anti-seed antibody

Assembly and deposition of amyloid β-protein (Aβ) in the brain is a fundamental process of Alzheimer’s disease (AD). We previously hypothesized that GM1 ganglioside-bound Aβ (GAβ) is an endogenous seed for Aβ assembly in brain. Recently, we have succeeded in generation of a monoclonal antibody specific to GAβ. Notably, this antibody, 4396C, per se substantially inhibits Aβ assembly in vitro. Here we report that the peripheral administration of Fab fragments of 4396C into transgenic mice expressing a mutant amyloid precursor protein gene, following the conjugation of the protein transduction domain of the Tat protein, markedly suppressed Aβ deposition in the brain. This result further supports our previous hypothesis and also provides a new insight into develop AD therapy through targeting seed Aβ in the brain, which selectively inhibits the initial step of the pathological process of AD.

Comparative analysis of cortical gene expression in mouse models of Alzheimer's disease

Three mouse models of Alzheimer's disease (AD) were used to assess changes in gene expression potentially critical to amyloid β-peptide (Aβ)-induced neuronal dysfunction. One mouse model harbored homozygous familial AD (FAD) knock-in mutations in both, amyloid precursor protein (APP) and presenilin 1 (PS-1) genes (APP NLh/NLh/PS-1 P264L/P264L), the other two models harbored APP over-expression of FAD mutations (Tg2576) with the PS-1 knock-in mutation at either one or two alleles. These mouse models of AD had varying levels of Aβ40 and Aβ42 and different latencies and rates of Aβ deposition in brain. To assess changes in gene expression associated with Aβ accumulation, the Affymetrix murine genome array U74A was used to survey gene expression in the cortex of these three models both prior to and following Aβ deposition. Altered genes were identified by comparing the AD models with age-matched control littermates. Thirty-four gene changes were identified in common among the three models in mice with Aβ deposition. Among the up-regulated genes, three major classes were identified that encoded for proteins involved in immune responses, carbohydrate metabolism, and proteolysis. Down-regulated genes of note included pituitary adenylate cyclase-activating peptide (PACAP), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor I receptor (IGF-IR). In young mice without detectable Aβ deposition, there were no regulated genes common among the three models, although 40 genes were similarly altered between the two Tg2576 models with the PS-1 FAD knock-in. Finally, changes in gene expression among the three mouse models of AD were compared with those reported in human AD samples. Sixty-nine up-regulated and 147 down-regulated genes were found in common with human AD brain. These comparisons across different genetic mouse models of AD and human AD brain provide greater support for the involvement of identified gene expression changes in the neuronal dysfunction and cognitive deficits accompanying amyloid deposition in mammalian brain.

Assembly of hereditary amyloid β-protein variants in the presence of favorable gangliosides

The mechanisms underlying regional amyloid β-protein (Aβ) deposition in brain remain unclear. Here we show that assembly of hereditary variant Dutch- and Italian-type Aβs, and Flemish-type Aβ was accelerated by GM3 ganglioside, and GD3 ganglioside, respectively. Notably, cerebrovascular smooth muscle cells, which compose the cerebral vessel wall at which the Dutch- and Italian-type Aβs deposit, exclusively express GM3 whereas GD3 is upregulated in the co-culture of endothelial cells and astrocytes, which forms the cerebrovascular basement membrane, the site of Flemish-type Aβ deposition. Our results suggest that regional Aβ deposition is induced by the local gangliosides in the brain.

Estrogen Therapy Fails to Alter Amyloid Deposition in the PDAPP Model of Alzheimer’s Disease

Epidemiological studies implicate estrogen deprivation as a risk factor for Alzheimer's disease and postmenopausal estrogen replacement as protective factor. One potential mechanism involves estrogen attenuation of beta-amyloid (Abeta) peptide accumulation. We examined the effect of estrogen on amyloid accumulation in female PDAPP mice, which express human amyloid precursor protein (APP) with the V717F mutation. These animals deposit Abeta 1-42 in the hippocampus and neocortex and develop Alzheimer-like neuropathology. Mice were subjected to ovariectomy, ovariectomy with estrogen replacement, or sham surgery at 3 months of age, and levels of cerebral Abeta 1-40 and 1-42 were determined after 5 months of treatment. Neither estrogen deprivation nor estrogen replacement altered Abeta accumulation in the hippocampus or neocortex. Similarly, immunoreactivity for full-length human APP and secreted APPalpha was unchanged. Estrogen status of the animals was confirmed using a variety of techniques, including uterine and pituitary weight, vaginal cytology, and plasma estradiol concentrations. There was no correlation between plasma estradiol levels and accumulation of either Abeta 1-40 or Abeta 1-42 in the brain. Our observations indicate that long-term estrogen therapy does not alter amyloid pathology in PDAPP mice, an animal model of Alzheimer's disease, and question the role of estrogen in Abeta deposition in brain.

Lifelong immunization with human β-amyloid (1–42) protects Alzheimer's transgenic mice against cognitive impairment throughout aging

Although both active and passive β-amyloid (Aβ) immunotherapy have been shown to protect against or lessen cognitive impairment in various Alzheimer's transgenic mouse lines, these studies have focused on a single task and involved standard statistical analysis. Because Alzheimer's disease impacts multiple cognitive domains, the current study employed an extensive behavioral battery and multimetric analysis therein to determine the impact of Aβ immunization given throughout most of adult life (from 2–16½ months of age) to APP+PS1 transgenic mice. At both adult (4½–6 month) and aged (15–16½ month) test points, the same 6-week behavioral battery was administered. Results indicate that Aβ immunotherapy partially or completely protected APP+PS1 mice at both test points from otherwise impaired performance in a variety of tasks spanning multiple cognitive domains (reference learning/memory, working memory, search/recognition). At both adult and aged test points, the cognitive benefits of Aβ immunotherapy were evident even when behavioral measures were analyzed collectively (as “overall” performance) through discriminant function analysis. Since behavioral protection at the 15–16½ month test point occurred without a decrease in (or correlation to) Aβ deposition, the mechanism of Aβ immunotherapy's action most likely involves neutralization/removal of small Aβ oligomers from the brain. However, in factor analysis performed at this aged test point, brain Aβ deposition measures loaded heavily with key cognitive measures. Collectively, our results suggest that the entire process of Aβ deposition deleteriously impacts cognitive performance and that Aβ-based preventative strategies can provide long-term cognitive benefits extending well into older age.

Sequence variants of IDE are associated with the extent of β-amyloid deposition in the Alzheimer's disease brain

Insulin degrading enzyme, encoded by IDE, plays a primary role in the degradation of amyloid β-protein (Aβ), the deposition of which in senile plaques is one of the defining hallmarks of Alzheimer's disease (AD). We recently identified haplotypes in a broad linkage disequilibrium (LD) block encompassing IDE that associate with several AD-related quantitative traits. Here, by examining 32 polymorphic markers extending across IDE and testing quantitative measures of plaque density and cognitive function in three independent Swedish AD samples, we have refined the probable position of pathogenic sequences to a 3′ region of IDE, with local maximum effects in the proximity of marker rs1887922. To replicate these findings, a subset of variants were examined against measures of brain Aβ load in an independent English AD sample, whereby maximum effects were again observed for rs1887922. For both Swedish and English autopsy materials, variation at rs1887922 explained approximately 10% of the total variance in the respective histopathology traits. However, across all clinical materials studied to date, this variant site does not appear to associate directly with disease, suggesting that IDE may affect AD severity rather than risk. Results indicate that alleles of IDE contribute to variability in Aβ deposition in the AD brain and suggest that this relationship may have relevance for the degree of cognitive dysfunction in AD patients.