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PubMed2005

Associative and motor learning in 12-month-old transgenic APP+PS1 mice.

Doubly transgenic 12-month-old amyloid precursor protein and presenilins 1 (APP+PS1) mice (n=14) and littermate control mice (n=17) were tested on eyeblink classical conditioning-a task impaired in humans with Alzheimer's disease (AD). Mice were also tested on a motor learning task (rotorod) and on sensory tasks (prepulse inhibition [PPI] and acoustic startle). Transgenic mice had impaired motor performance on rotorod. Overall, APP+PS1 mice performed similarly to controls on both 500ms delay and 500ms trace eyeblink conditioning as well as on prepulse inhibition (PPI) and acoustic startle. However, within the transgenic group, cortical amyloid burden correlated significantly with decreased trace eyeblink conditioning. Moreover, cortical amyloid burden and hippocampal microglia activation correlated significantly with decreased PPI. These data suggest that only those transgenic mice with the most severe amyloid pathology exhibited deficits in hippocampus-dependent tasks. Transgenic mouse models of amyloid deposition differ from Alzheimer patients not only by the absence of major neuronal loss, but also by the general absence of severe impairments in eyeblink conditioning, except for mice with the greatest amyloid pathology.

Alzheimer Disease↗
PubMed2006

Dendrimeric Abeta1-15 is an effective immunogen in wildtype and APP-tg mice.

Immunization of humans and APP-tg mice with full-length beta-amyloid (Abeta) results in reduced cerebral Abeta levels. However, due to adverse events in the AN1792 trial, alternative vaccines are required. We investigated dendrimeric Abeta1-15 (dAbeta1-15), which is composed of 16 copies of Abeta1-15 peptide on a branched lysine core and thus, includes an Abeta-specific B cell epitope but lacks the reported T cell epitope. Immunization by subcutaneous, transcutaneous, and intranasal routes of B6D2F1 wildtype mice led to anti-Abeta antibody production. Antibody isotypes were mainly IgG1 for subcutaneous or transcutaneous immunization and IgG2b for intranasal immunization, suggestive of a Th2-biased response. All Abeta antibodies preferentially recognized an epitope in Abeta1-7. Intranasal immunization of J20 APP-tg mice resulted in a robust humoral immune response with a corresponding significant reduction in cerebral plaque burden. Splenocyte proliferation against Abeta peptide was minimal indicating the lack of an Abeta-specific cellular immune response. Anti-Abeta antibodies bound monomeric, oligomeric, and fibrillar Abeta. Our data suggest that dAbeta1-15 may be an effective and potentially safer immunogen for Alzheimer's disease (AD) vaccination.

Administration, Cutaneous↗
PubMed2004

Niemann-Pick Type C disease and Alzheimer's disease: the APP-endosome connection fattens up.

Niemann-Pick Type C (NPC) is an inherited neurodegenerative disease of childhood and adolescence that develops from a failure of cholesterol trafficking within the endosomal-lysosomal pathway. Although NPC differs in major respects from Alzheimer's disease (AD), intriguing parallels exist in the cellular pathology of these two diseases, including neurofibrillary tangle formation, prominent lysosome system dysfunction, and influences of apolipoprotein E epsilon4 genotype. Added to these similarities are new findings that some neuronal populations develop abnormalities of endosomes resembling those seen at the earliest stages of AD and also accumulate beta-cleaved amyloid precursor protein (APP) and Abeta peptides within endosomes. In this commentary, the common features of endosome dysfunction are reviewed. Emerging evidence that endosome dysfunction may lead to beta-amyloidogenic APP processing or neurodegeneration by several different means is discussed.

Adolescent↗
PubMed2000

Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons.

Deposition of amyloid beta-peptide (Abeta) in cerebral vessel walls (cerebral amyloid angiopathy, CAA) is very frequent in Alzheimer's disease and occurs also as a sporadic disorder. Here, we describe significant CAA in addition to amyloid plaques, in aging APP/Ld transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP) exclusively in neurons. The number of amyloid-bearing vessels increased with age, from approximately 10 to >50 per coronal brain section in APP/Ld transgenic mice, aged 13 to 24 months. Vascular amyloid was preferentially deposited in arterioles and ranged from small focal to large circumferential depositions. Ultrastructural analysis allowed us to identify specific features contributing to weakening of the vessel wall and aneurysm formation, ie, disruption of the external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells. Biochemically, the much lower Abeta42:Abeta40 ratio evident in vascular relative to plaque amyloid, demonstrated that in blood vessel walls Abeta40 was the more abundant amyloid peptide. The exclusive neuronal origin of transgenic APP, the high levels of Abeta in cerebrospinal fluid compared to plasma, and the specific neuroanatomical localization of vascular amyloid strongly suggest specific drainage pathways, rather than local production or blood uptake of Abeta as the primary mechanism underlying CAA. The demonstration in APP/Ld mice of rare vascular amyloid deposits that immunostained only for Abeta42, suggests that, similar to senile plaque formation, Abeta42 may be the first amyloid to be deposited in the vessel walls and that it entraps the more soluble Abeta40. Its ability to diffuse for larger distances along perivascular drainage pathways would also explain the abundance of Abeta40 in vascular amyloid. Consistent with this hypothesis, incorporation of mutant presenilin-1 in APP/Ld mice, which resulted in selectively higher levels of Abeta42, caused an increase in CAA and senile plaques. This mouse model will be useful in further elucidating the pathogenesis of CAA and Alzheimer's disease, and will allow testing of diagnostic and therapeutic strategies.

Aging↗
PubMed2003

Both raft- and non-raft proteins associate with CHAPS-insoluble complexes: some APP in large complexes.

Components of caveolae and lipid rafts are characterized by their buoyancy after detergent extraction. Using flotations in density gradients, we now show that non-raft membrane molecules are also associated with detergent-insoluble, buoyant assemblies. When Triton X-100 cellular extracts were spun to equilibrium in Nycodenz, only components of classical rafts floated. In contrast, with the zwitterionic detergent CHAPS, non-raft residents such as calnexin and APP also buoyed. When CHAPS extracts were spun in non-equilibrium (velocity) conditions, some raft components rapidly exited the input fractions while other raft markers and non-raft molecules remained relatively immobile. This pointed to size heterogeneities of CHAPS-insoluble complexes. Combined velocity/equilibrium gradients broadly divided CHAPS-insoluble membrane complexes into three size categories, which all contained cholesterol and the glycosphingolipid GM1. Large complexes were enriched in caveolin and ESA. Medium size complexes were enriched in PrP, whereas small complexes contained non-raft proteins, PrP, and some ESA. While Alzheimer's APP was primarily confined to small assemblies, a portion of its glycosylated form did buoy with large complexes. Large CHAPS-insoluble complexes resemble, but are not equal to, classical rafts. These findings extend considerably the range of detergent-insoluble membranal domains.

Amyloid↗
PubMed2003

APP intracellular domain formation and unaltered signaling in the presence of familial Alzheimer's disease mutations.

One of the cardinal neuropathological findings in brains from Alzheimer's disease (AD) patients is the occurrence of amyloid beta-peptide (Abeta) deposits. The gamma-secretase-mediated intramembrane proteolysis event generating Abeta also results in the release of the APP intracellular domain (AICD), which may mediate nuclear signaling. It was recently shown that AICD starts at a position distal to the site predicted from gamma-secretase cleavage within the membrane. This novel site, the epsilon site, is located close to the inner leaflet of the membrane bilayer. The relationship between proteolysis at the gamma and epsilon sites has not been fully characterized. Here we studied AICD signaling in intact cells using a chimeric C99 molecule and a luciferase reporter system. We show that the release of AICD from the membrane takes place in a compartment downstream of the endoplasmic reticulum, is dependent on presenilin proteins, and can be inhibited by treatment with established gamma-secretase inhibitors. Moreover, we find that AICD signaling remains unaltered from C99 derivatives containing mutations associated with increased Abeta42 production and familial AD. These findings indicate that there are very similar routes for Abeta and AICD formation but that FAD-linked mutations in APP primarily affect gamma-secretase-mediated Abeta42 formation, and not AICD signaling.

Alzheimer Disease↗
PubMed1997

Cerebellar pathology in sporadic and familial Alzheimer's disease including APP 717 (Val-->Ile) mutation cases: a morphometric investigation.

Familial Alzheimer's disease (FAD) tends to present with more prominent neurological symptoms including cerebellar signs than sporadic Alzheimer's disease (SAD). In order to elucidate the pathological differences in the cerebellum, which may be associated with the cerebellar symptoms, we have investigated morphometrically beta-amyloid deposits, atrocytosis, Purkinje cells and dentate neurons in the cerebellum of 10 FAD patients including two cases with the beta-amyloid precursor protein (APP) gene mutation (APP717 Val-->Ile), 10 SAD patients and 10 non-demented age-matched controls. The regions examined included the molecular, Purkinje cell and granular cell layers, the cerebellar white matter and the dentate nucleus. Purkinje cell density in FAD was significantly lower than in SAD. There were no significant differences in the density of dentate neurons among the three groups. The density of astrocytes in FAD was significantly greater than that in SAD in the granular cell and Purkinje cell layers and in the white matter. There were no significant differences in the amount and subtypes of beta-amyloid deposits (extracellular, vascular and perivascular) between FAD and SAD in all the regions investigated. In two cases with the APP mutation, both Purkinje cell loss and beta-amyloid deposition in the cerebellum were greater than the mean for FAD and SAD cases. Astrocytosis in the mutation cases was not greater than the mean for FAD cases except for the dentate nucleus in one case. Extracellular beta-amyloid deposits were not seen in any of the control cases although amyloid angiopathy was observed in one case. This study demonstrates for the first time that Purkinje cell loss and reactive astrocytosis of the cerebellum in FAD are more severe than in SAD, but that beta-amyloid deposition in the cerebellum in both FAD and SAD are similar. The more prominent neurological signs observed in FAD may be explained by more severe neurodegeneration than are found in sporadic cases.

Aged↗
PubMed2002

Alzheimer's disease and Down's syndrome: roles of APP, trophic factors and ACh.

Recent therapeutic investigations of Alzheimer's disease (AD) have been guided by two seemingly opposed hypotheses: the amyloid cascade theory, which favors the amyloid plaques as the cause of AD; and the cholinergic theory, which favors cholinergic neuron loss as the cause. New investigations indicate that the synthesis and processing of the amyloid precursor protein (APP) is linked to the trophic actions of nerve growth factor. A pathological cascade in both AD- and Down's syndrome-related memory loss could be triggered by alterations in APP processing or ACh-mediated neuronal function, or both, which in turn trigger the overexpression of amyloid beta, synaptic malfunction and trophic factor loss in target regions. This eventually leads to synaptic and dendritic loss with age.

Acetylcholine↗
PubMed1997

IL-6 and APPs: anti-inflammatory and immunosuppressive mediators.

Acute inflammation is accompanied by changes in the concentrations of acute phase proteins (APPs). While much is known about the cytokines involved in the initiation of inflammation, less is known about the mediators involved in its resolution. Recent data suggest that interleukin 6 (IL-6) and IL-6-regulated APPs are anti-inflammatory and immuno-suppressive, and may negatively regulate the acute phase response.

Acute-Phase Proteins↗
PubMedDate not supplied

Intrahippocampal LPS injections reduce Abeta load in APP+PS1 transgenic mice.

Multiple lines of evidence indicate that inflammatory processes are involved in the pathogenesis of Alzheimer's disease. Lipopolysaccharide (LPS) is widely used to induce inflammation in experimental systems. Consequently we injected LPS or saline intrahippocampally in 11 and 16 months old APP+PS1 transgenic mice to induce brain inflammation, then used immunocytochemistry to examine amyloid pathology 7 days later. As expected, LPS activated microglia as indicated by a significant increase in the area covered by major histocompatibility complex-II (MHC-II) immunostaining in the mice injected with LPS compared to the saline injected. Simultaneously, Abeta immunostaining showed an unexpected reduction of the Abeta load in the mice injected with LPS compared to the saline injected. This effect of LPS on the Abeta load in APP+PS1 mice strengthens the hypothesis that moderate amounts of microglial activation may be beneficial in Alzheimer's disease, by increasing the clearance of Abeta.

Amyloid beta-Peptides↗
PubMed2002

APP transgenic mice Tg2576 accumulate Abeta peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques.

The amyloid (Abeta) peptides generated in Hsiao's APP Tg2576 transgenic (Tg) mice are physically and chemically distinct from those characteristic of Alzheimer's disease (AD). Transgenic mouse Abeta peptides were purified using sequential size-exclusion and reverse-phase chromatographic systems and subjected to amino acid sequencing and mass spectrometry analyses. The mouse Abeta peptides lacked the extensive N-terminal degradations, posttranslational modifications, and cross-linkages abundant in the stable Abeta peptide deposits observed in AD. Truncated Abeta molecules appear to be generated in vivo by hydrolysis at multiple sites rather than by post-mortem C-terminal degradation. In contrast to AD amyloid cores, the Tg mice peptides were soluble in Tris-SDS-EDTA solutions, revealing both monomeric and SDS-stable oligomeric species of Abeta. In contrast to our report on Novartis Pharma APP23 Tg mice [Kuo et al. (2001) J. Biol. Chem. 276, 12991], which maintain high levels of soluble Abeta early on with later development of extensive vascular amyloid, Tg2576 mice exhibited an age-related elevation of soluble Abeta with relatively limited vascular amyloid deposition. The transgenic mouse levels of carboxy-terminal (CT) APP fragments were nearly 10-fold greater than those of human brains, and this condition may contribute to the unique pathology observed in these animals. Immunization of transgenic mice may act to prevent the pathological effects of betaAPP overproduction by binding CT molecules or halting their processing to toxic forms, in addition to having any effects on Abeta itself. Thus, differences in disease evolution and biochemistry must be considered when using transgenic animals to evaluate drugs or therapeutic interventions intended to reduce the Abeta burden in Alzheimer's disease.

Alzheimer Disease↗
PubMed2003

The transcriptional activity of the APP intracellular domain-Fe65 complex is inhibited by activation of the NF-kappaB pathway.

The beta-amyloid precursor protein (APP) is an integral membrane protein that is the subject of proteolytic processing. Sequential cleavage of APP by beta-secretase and subsequently gamma-secretase generates the beta-amyloid peptide as well as a cytoplasmic intracellular domain (AICD). AICD binds to the transcriptional coactivator Fe65, and this complex has been shown to display transcriptional activity. The regulation of this complex is poorly understood. We show here that activation of the NF-kappaB pathway, either by overexpression of NF-kappaB-inducing kinase (NIK) or by treatment with the proinflammatory cytokine IL-1beta, downregulates the transcriptional activity of the AICD-Fe65 complex. This therefore provides a mechanism by which the activity of AICD might be modulated by extracellular stimuli. These results also identify an intracellular signal transduction pathway influenced by the NF-kappaB signaling pathway.

Amyloid beta-Protein Precursor↗
PubMed2003

Catalytic site-directed gamma-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and beta-APP cleavages.

The generation of gamma-secretase inhibitors which block the release of beta-amyloid peptide (Abeta) has long been an attractive therapeutic avenue for treatment or prevention of Alzheimer's disease (AD). Such inhibitors would reduce levels of Abeta available for aggregation into toxic assemblies that lead to the plaque pathology found in affected brain tissue. Cumulative evidence suggests that the S3 cleavage of Notch is also dependent on presenilins (PS) and is carried out by the multimeric PS-containing gamma-secretase complex. It is therefore possible that Notch function could be affected by gamma-secretase inhibitors. To assess the relationship between the cleavage of these substrates in the same system, Western blot cleavage assays have been established using a human cell line stably expressing both the beta-amyloid precursor protein (beta-APP) and the truncated Notch1 receptor fragment NotchDeltaE. Thus, a direct correlation may be made, following inhibitor treatment, of the decrease in the levels of the cleavage products, Abeta peptide and the Notch intracellular domain (NICD), as well as the increase in stabilized levels of both substrates. This analysis has been performed with a range of selected gamma-secretase inhibitors from six distinct structural classes. Changes in all four species usually occur in concert and with remarkably good agreement. A significant cleavage window is not clearly apparent in any case. Thus, these Notch and beta-APP cleavages cannot be dissected apart easily since they show the same pharmacological profile of inhibition. Whether this translates into proportionally reduced Notch signaling in vivo, however, remains to be seen.

Alzheimer Disease↗
PubMed2003

Increased fibrillar beta-amyloid in response to human clq injections into hippocampus and cortex of APP+PS1 transgenic mice.

Human C1q when injected directly into hippocampus and cortex of doubly transgenic APP+PS1 mice results in the increase of Congo red-positive fibrillar deposits. Although there was no significant change in overall area stained for Abeta total, qualitatively it appeared that there was less diffuse Abeta in C1q-treated mice versus vehicle. There was no apparent change in astroglial or microglial activation caused by injection of C1q with respect to vehicle injections. These effects of C1q were only found in 50% BUB/BnJ mice, a strain with higher serum complement activity than other mouse lines. These in vivo data were consistent with the effects of C1q to increase fibrillogenesis of Abeta in vitro. In conclusion, complement protein C1q, believed to be involved in the pathogenesis of Alzheimer's disease in humans, can cause increased fibrillogenesis in the APP+PS1 mouse model of amyloid deposition.

Amyloid beta-Peptides↗
PubMed2003

APP processing enzymes (secretases) as therapeutic targets: insights from the use of transgenics (Tgs) and transfected cells.

Secretases degrade amyloid precursor protein (APP) releasing fragments (beta-peptides A beta, A beta x) that assemble to form hallmark extracellular deposits in Alzheimer's disease (AD) correlating with disease severity. As such, secretases supply targets for therapeutic intervention and form the focus of this overview. Progress in elucidating secretases and their modes of catalysis come from exploiting the use of transgenics or transfected cells. In addition to A beta x, secretases also release C-terminal fragments with putative signaling properties (amyloid intracellular domain, AICD) similar in concept to those available for conversion of the Notch-r to release the nuclear transactivator NICD. The review considers lingering questions on APP fragmentation by secretase action, ancillary proteins such as presenilins (PS1/2), nicastrin, XII, or proteases (caspases), and the influence of familial mutations (mAPP, mPS) in terms of fibrillogenesis.

Alzheimer Disease↗
PubMed2003

Learning and memory deficits in APP transgenic mouse models of amyloid deposition.

Several different transgenic APP mice develop learning and memory deficits. In some cases the mice have deficits very early in life, while in other instances the mice exhibit deficits only after they have aged and amyloid deposits have accumulated. In many cases, there is a correlation in individual mice of the same age and genotype between the extent of learning and memory deficits and the amounts of deposited amyloid found in the central nervous system. While superficially this might imply that the deposited material is somehow toxic to cognition, it is likely that deposited amyloid is also an index of the overall rate of amyloid production in each mouse. Rate of production would be expected to modify not only the amounts of deposited amyloid, but also other amyloid pools, including soluble, oligomeric, conjugated (e.g. ADDLs) and intracellular. Thus, the deposited material may be an integrated reflection of total A beta production, in addition to indicating the amounts in fibrillar forms. As such, it is conceivable that other A beta pools may be more directly linked to memory deficits. Thus far, the one manipulation found to mitigate the learning and memory deficits in APP transgenic mice is immunotherapy for A beta, either using active or passive immunization against the peptide. These data together with other findings are leading to a conclusion that the fibrillar A beta deposits are not directly linked to the memory deficits in mice, and that some other A beta pool, more readily diminished by immunotherapy, is more directly linked to the mechanisms leading to poor performance in learning and memory tasks.

Amyloid beta-Peptides↗
PubMedDate not supplied

Germline mutational analysis of presenilin 1 and APP genes in Jewish-Israeli individuals with familial or early-onset Alzheimer disease using denaturing gradient gel electrophoresis (DGGE).

Germ line mutations in three genes have been detected in patients with familial Alzheimer's disease (FAD) and sporadic, early onset disease: amyloid precursor protein (APP), presenilin 1 (PS-1), and presenilin 2 (PS-2). The relative proportions in which mutations in these genes occur among AD patients in Israel has not been evaluated. To that end, we screened 52 Jewish-Israeli patients with AD: 22 with sporadic, early-onset disease (below 65 years), and 30 with FAD. Mutation screen employed denaturing gradient gel electrophoresis (DGGE) of exon-specific PCRs and restriction enzyme digest. Five patients from three different families displayed mutations within the PS-1 gene: three patients of one family showed a mis-sense mutation in codon 120 (Glu 120Lys), and two other unrelated patients showed an identical mis-sense mutation in codon 318 (Glu318Gly). No patient showed an abnormal migration on DGGE (for APP) or mutant restriction digest pattern (for PS-2) genes. These data may indicate the existence of another familial Alzheimer disease (FAD) gene locus in the Israeli Jewish population.

Adult↗
PubMed2003

Identification of phospholipid scramblase 1 as a novel interacting molecule with beta -secretase (beta -site amyloid precursor protein (APP) cleaving enzyme (BACE)).

beta-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) is an integral membrane aspartic proteinase responsible for beta-site processing of APP, and its cytoplasmic region composed of 24 amino acid residues has been shown to be involved in the endosomal localization of BACE. With the yeast two-hybrid screening, we found that the cytoplasmic domain of phospholipid scramblase 1 (PLSCR1), a type II integral membrane protein, interacts with the cytoplasmic region of BACE. In cultured cells, BACE and PLSCR1 were colocalized in the Golgi area and in endosomal compartments, whereas they were co-redistributed in late endosome-derived multivesicular bodies when treated with U18666A, suggesting that both proteins share a common trafficking pathway in cells. Co-immunoprecipitation analysis showed that both proteins form a protein complex at an endogenous expression level in the human neuroblastoma SH-SY5Ycells, and the dileucine residue of the BACE tail is also revealed to be essential for the physical interaction with PLSCR1 in vitro and in vivo. Moreover, both BACE and PLSCR1 were localized in a low buoyant lipid microdomain in SH-SY5Y cells. The dileucine-defective BACE mutant was also fractionated into the lipid microdomain, but much less stably than wild-type BACE. Taken together, our current study suggests the functional involvement of PLSCR1 in the intracellular distribution of BACE and/or recruitment of BACE into the detergent-insoluble lipid raft.

Amyloid Precursor Protein Secretases↗