Search PubMed⌕ Search

Biomedical subjects

Z Suo

Publications and source records attributed to Z Suo.

At least 37 records · Page 2Linked to original sources
PubMed2000

Gender-specific association of the angiotensin converting enzyme gene with Alzheimer's disease.

Epidemiological studies have demonstrated that risk factors for vascular disease are also risk factors for Alzheimer's disease (AD). The gene for the angiotensin converting enzyme (ACE) has recently been reported to be associated with risk for AD. We have investigated the possibility of such an association in 98 clinic-based and 73 community-based AD cases versus 175 community-based controls and find a gender-specific association of ACE genotype with AD in the female clinic population. These data suggest that gender may interact with genetic factors to influence risk for AD. Gender-specific risk for AD has been previously reported, and a biological rationale for involvement of ACE in the AD process is supported by studies exploring the relationship between AD and vascular risk factors such as hypertension. However, the results may also be a consequence of the known anomalies that arise in genetic association studies as a consequence of sample selection.

Alzheimer Disease↗
PubMed2000

A beta vasoactivity in vivo.

Bilateral temporoparietal hypoperfusion has been frequently observed early in the Alzheimer's disease (AD) process. The beta-amyloid (A beta) peptide is believed to play a central role in the pathogenesis of AD. In vitro experiments have shown that freshly solubilized A beta enhances constriction of cerebral and peripheral vessels. We proposed that in vivo, A beta would also have vasoactive properties. To test this hypothesis, we intraarterially infused freshly solubilized A beta 1-40 in rats and observed changes in peripheral blood pressure, cerebral blood flow, and cerebrovascular resistance. We found that infusion of A beta in vivo significantly increased the blood pressure in hypotensive rats but not in normotensive and hypertensive rats. Moreover, A beta infusion also resulted in a decreased blood flow and increased vascular resistance specifically in cerebral cortex but not in heart or kidneys. These data suggest that A beta has a direct and specific constrictive effect on cerebral vessels in vivo, which may contribute to the cerebral hypoperfusion observed early in the AD process.

Amyloid↗
PubMed1999

Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation.

Alzheimer's disease (AD) has a substantial inflammatory component, and activated microglia may play a central role in neuronal degeneration. CD40 expression was increased on cultured microglia treated with freshly solublized amyloid-beta (Abeta, 500 nanomolar) and on microglia from a transgenic murine model of AD (Tg APPsw). Increased tumor necrosis factor alpha production and induction of neuronal injury occurred when Abeta-stimulated microglia were treated with CD40 ligand (CD40L). Microglia from Tg APPsw mice deficient for CD40L demonstrated reduction in activation, suggesting that the CD40-CD40L interaction is necessary for Abeta-induced microglial activation. Finally, abnormal tau phosphorylation was reduced in Tg APPsw animals deficient for CD40L, suggesting that the CD40-CD40L interaction is an early event in AD pathogenesis.

Alzheimer Disease↗
PubMed1999

Tandem heterocyclization activity of the multidomain 230 kDa HMWP2 subunit of Yersinia pestis yersiniabactin synthetase: interaction of the 1-1382 and 1383-2035 fragments.

The six-domain, 2035-amino acid subunit high-molecular weight protein 2 (HMWP2) activates salicylate and two cysteines and loads them covalently on its three carrier protein domains during assembly of the iron-chelating virulence factor, yersiniabactin of the plague bacterium Yersinia pestis. The 1-1382 fragment of HMWP2 (ArCP-Cy1-A), overproduced in Escherichia coli, contains the first three domains: the aryl carrier protein (ArCP) domain, the cysteine specific adenylation domain (A), and the first condensation/cyclization domain (Cy1). The ArCP can be posttranslationally phosphopantetheinylated on Ser52 and then loaded with a salicyl group on the phosphopantetheine (Ppant) thiol by action of the YbtE, a salicyl-AMP ligase. The HMWP2 1-1382 fragment can activate L-cysteine as Cys-AMP. The HMWP2 1383-2035 fragment contains the remaining three domains: two peptidyl carrier proteins (PCP1 and PCP2) separated by a second condensation/cyclization domain (Cy2). Phosphopantetheinylation of the HMWP2 1383-2035 fragment at Ser1439 (PCP1) and Ser1977 (PCP2) facilitates cysteinylation of both thiols by HMWP2 1-1382. When the holo 1-1382 and bis-holo 1383-2035 protein fragments are mixed with ATP, salicylate, and cysteine, four products are slowly released [salicylcysteine (Sal-Cys), (hydroxyphenylthiazolinyl)cysteine (HPT-Cys), HPT-Cys-Cys, and the bisheterocyclic HPTT-Cys], reflecting thiolytic rerouting by cysteine in solution of elongating acyl-S-enzyme intermediates tethered at ArCP, PCP1, and PCP2 carrier protein domains, respectively. Conducting the in trans reconstitution with the S1439A mutant of HMWP2 1383-2035 releases only Sal-Cys, while the S1977A mutant leads to HPT-Cys formation but not HPT-Cys-Cys or HPTT-Cys. These results suggest localization of particular acyl-S-enzyme intermediates to each of the three carrier protein regions and also establish the sequential action of Cy1 and Cy2, with the latter producing the tandem 4,2-bisheterocyclic hydroxyphenylthiazolinylthiazolinyl (HPTT) moiety characteristic of this class of siderophores.

Acyl Carrier Protein↗
PubMed1999

Induction of CD40 on human endothelial cells by Alzheimer's beta-amyloid peptides.

Growing evidence suggests that beta-amyloid (Abeta) peptides play a central role in mediating vascular endothelium dysfunction, but the extent to which immune mechanisms are involved in this process remains unclear. To explore such mechanisms, we incubated cultured human aortic endothelial cells (HAEC) with freshly solublized Abeta and examined expression of a central immunoregulatory molecule, CD40, in these cells using reverse transcriptase-polymerase chain reaction, Western immunoblotting, and Flow cytometry. Our results show that treatment of endothelial cells with Abeta1-40, Abeta1-42 or gamma interferon (IFN-gamma) results in a dose-dependent induction of endothelial CD40 expression. Furthermore, ligation of endothelial CD40 and simultaneous treatment of human endothelial cells with IFN-gamma or Abeta peptides leads to a significant release of interleukin-1beta (IL-1beta), a marker for endothelial cell activation. Since IL-1beta is an important inflammatory response mediator, these findings suggest that the functional role of Abeta-induced endothelial CD40 may be promotion of the inflammatory cascade in vascular endothelial cells.

Alzheimer Disease↗
PubMed1999

Single d(GpG)/cis-diammineplatinum(II) adduct-induced inhibition of DNA polymerization.

A 44 nucleotide DNA template containing a single site-specifically placed cisplatin adduct (cis-[Pt(NH3)2[d(GpG)-N7(1),-N7(2)]]) was annealed with a primer, positioning its 3'-end four bases before the adduct in the template strand. DNA polymerization in the presence of all four nucleotides revealed that both HIV-1 reverse transcriptase (RT) and T7 DNA polymerase strongly paused at one nucleotide preceding the first platinated guanine and at the positions opposite the two platinated guanines. Analysis of single nucleotide incorporation at each pause site showed that polymerization occurs with biphasic kinetics. A small percentage of DNA was bound productively, providing a small amplitude (1-3%) of a fast phase of polymerization, whereas most of the bound DNA (1-34%) was positioned at the pause site in a nonproductive manner and therefore elongated slowly (0.04-0.06 s-1). DNA substrates annealed to the cisplatin-modified template bind to HIV-1 RT with an affinity (10-20 nM) similar to that of unmodified substrates (6-9 nM). The cisplatin-DNA cross-link moderately weakened DNA binding to T7 DNA polymerase (12-115 nM) but significantly slowed the rate of incorporation of the next nucleotide (2-7 s-1 ), with larger effects closer to the cisplatin-DNA adduct. The crystal structure of the same cisplatin-DNA adduct [Takahara, P. M., Frederick, C. A., and Lippard, S. J. (1996) J. Am. Chem. Soc. 118, 12309-12321] reveals not only the bent DNA duplex but also the propeller twisted base pairs near the cisplatin-DNA adduct. The twisted base pairs may cause misalignment of the cisplatin-modified DNA at the binding cleft of T7 DNA polymerase and significantly slow the rate of the protein conformational change preceding polymerization, leading to the slight accumulation of intermediates within five base pairs of the adduct. The ground-state binding of the next correct nucleotide to the enzyme.DNA complex was weakened by the adduct with T7 DNA polymerase but unchanged with HIV-1 RT at sites other than the three strong pause sites. Nucleotide binding to both enzymes at the three strong pause sites was significantly weaker and less selective.

Bacteriophage T7↗
PubMed1999

Normobaric oxygen treatment during radiotherapy for carcinoma of the uterine cervix. Results from a prospective controlled randomized trial.

BACKGROUND AND PURPOSE: Hypoxia, a frequent characteristic of cervical cancer, is associated with reduced sensitivity to irradiation and thus may be a source of radiotherapy failure. This study was planned to test the hypothesis, that inhalation of oxygen during radiotherapy may increase the radiation effect on the tumor and improve loco-regional control and overall survival. MATERIAL AND METHODS: From 1963 to 1965, a consecutive series of 208 patients with cervical cancer stage II/III who were to be treated by external irradiation plus radium inserts, were included in this study. They were randomly assigned to either receive oxygen inhalations during the radiotherapy sessions or just breathing air. Due to technical reasons the oxygen group was divided. For the first 10 months, they did receive oxygen during the radium inserts only, the last 13 months during all radiotherapy sessions. RESULTS: After median 33 years follow-up, there are no differences in overall survival, cancer-specific survival or loco-regional control. Subgroup analysis shows significantly improved loco-regional control in the stage IIB patients, with squamous cell carcinoma who received oxygen during all radiotherapy sessions. This improvement was especially pronounced among the patients who also received blood transfusions. CONCLUSIONS: There was no influence of normobaric oxygen treatment on the overall outcome to radiotherapy in patients with stage II cervical cancer, but subgroup analyses support the hypothesis that there is tumor areas of hypoxia-based radioresistance that may be counteracted by oxygen administration.

Adult↗
PubMed1999

Human papillomavirus 16 in breast cancer of women treated for high grade cervical intraepithelial neoplasia (CIN III).

Women with both a history of high grade cervical intraepithelial neoplasia (CIN III) and breast carcinoma as second primary cancer were selected for studying the presence of HPV in breast carcinomas. Paraffin embedded material from 38 patients with 41 breast carcinoma cases after CIN III were examined by polymerase chain reaction (PCR) and in situ hybridization. By PCR we detected HPV 16 DNA in 19 out of 41 cases (46%) of the breast carcinomas. One case proved to be HPV 16 positive also by in situ hybridization. HPV 16 was also detected in 32 out of the 38 patients with CIN III (84%). All HPV 16 positive breast carcinomas were HPV 16 positive in their corresponding CIN III lesions. Eight patients with diagnosed breast cancer before the CIN III lesions were used as controls. None of these had HPV positive breast carcinomas. No cases were positive for HPV 11, 18, or 33. HPV 16 was detected in the primary tumours, in local metastases from HPV 16 positive tumours, in a distant HPV 16 positive breast carcinoma metastasis to the colon, and in other primary cancers in patients with HPV 16 positive breast carcinomas and HPV 16 positive CIN III. Estrogen and progesterone receptors were quantified in the HPV positive and HPV negative breast carcinomas, and there was no significant difference in the fraction positive in the two groups. Oncogenic HPV DNA might be transported from an original site of infection to other organs by blood or lymph, and possibly be a factor in the development of cancer in different organs.

Adult↗
PubMed1999

HPV positive bronchopulmonary carcinomas in women with previous high-grade cervical intraepithelial neoplasia (CIN III).

A significant higher incidence of some cancers, especially lung cancer, has been found in women with previous HPV-related (human papillomavirus) urogenital and anal neoplasias than in individuals without this particular clinical history. The aim of our study was to investigate whether HPV is present in both CIN III (cervical intraepithelial neoplasia) lesions and bronchopulmonary second primary cancers in women with a clinical history of both diseases. Paraffin-embedded tumour tissue from 75 patients with bronchopulmonary carcinomas was examined using the polymerase chain reaction (PCR) technique and in situ hybridization for the presence of human HPV. In total, 51 primary tumours without metastases, 11 primary tumours with metastases and 13 lymph node metastases without available tissue from primary tumours were analysed. In our study 37/75 primary bronchopulmonary tumours (49%) were identified as HPV positive by the PCR method: 18 cases were purely HPV 16 positive (49%), 12 were purely HPV 6 positive (32%), 5 cases were HPV 16/6 positive (14%), 1 case was HPV 16/11 positive (2%) and 1 case was HPV 16/18 positive (2%). Fourteen metastases were HPV positive, and HPV 16, 11 and 6 were detected in both regional and distant metastases. Two of the HPV 16-positive metastases were brain metastases from two separate HPV 16-positive primary tumours; 35% of the HPV-positive cases were adenocarcinomas, 30% squamous cell carcinomas, 22% oat cell carcinomas, 5% large cell carcinomas, 3% anaplastic carcinoma, 3% low-differentiated carcinoma, and 3% malignant cylindroma. The CIN III lesions from 34 of the 37 HPV-positive bronchopulmonary carcinomas were analysed by PCR. The overall HPV positivity in the CIN III lesions was 74% (25/34 cases): 48% were purely HPV 16 positive, 24% purely HPV 6 positive, 24% HPV 16/6 positive and 4% were HPV 18 positive. Our results indicate that HPV is also involved in the development of bronchopulmonary cancers in women with a history of CIN III lesions.

Base Sequence↗
PubMed1999

Prognostic value of lymphoma-specific S-phase fraction compared with that of other cell proliferation markers.

The proliferation-associated antigens Ki67 (immunohistochemistry) and proliferative cell nuclear antigen (PCNA) (immunohistochemistry and immunoblotting) were analysed together with DNA synthesis (3H-thymidine incorporation) and cell-cycle distribution (tumour-specific S-phase fraction determined by flow cytometry) in lymph node suspensions from 63 patients with newly diagnosed B-Cell non-Hodgkin's lymphomas. Details of clinical parameters, treatment and patient outcome were available for all patients, and retrospectively analysed. Of the proliferation-associated parameters, only high S-phase fraction (p < 0.00001) and high PCNA expression by immunoblotting (p = 0.012) were predictive of a poor prognosis. Of the conventional parameters, high-grade malignancy, high International Prognostic Index (IPI) score, bulky disease and presence of B symptoms predicted a patient for poor survival. High S-phase fraction was predictive of a short survival for the low-grade lymphomas analysed separately (p < 0.00001), as well as for patients treated with an Adriamycin- and a non-Adriamycin-containing regimen (p < 0.005 for both groups). In a multivariate analysis, S-phase fraction (p = 0.00006), IPI score (p = 0.015) and B symptoms (p = 0.017) had independent prognostic values, but not histological grade.

Adult↗
PubMed1998

Soluble Alzheimers beta-amyloid constricts the cerebral vasculature in vivo.

Bilateral temporoparietal hypoperfusion has been frequently observed early in the Alzheimer's disease (AD) process. An increased beta-amyloid (Abeta) peptide is believed to play a central role in the pathogenesis of AD. In vitro experiments have shown that freshly solubilized Abeta enhances constriction of cerebral and peripheral vessels. We propose that in vivo the Abeta vasoactive property may contribute to cerebral hypoperfusion of AD patients. To test this hypothesis, we intra-arterially infused freshly solubilized Abeta -40 in rats and observed changes in cerebral blood flow and cerebrovascular resistance using fluorescent microspheres. We found that infusion of Abeta in vivo resulted in a decreased blood flow and increased vascular resistance specifically in cerebral cortex but not in heart or kidneys. These data suggest that Abeta has a direct and specific constrictive effect on cerebral vessels in vivo, which may contribute to the cerebral hypoperfusion observed early in the AD process.

Alzheimer Disease↗
PubMed1998

Selective inhibition of HIV-1 reverse transcriptase by an antiviral inhibitor, (R)-9-(2-Phosphonylmethoxypropyl)adenine.

(R)-9-(2-Phosphonylmethoxypropyl)adenine (PMPA) is an acyclic nucleoside phosphonate that has been shown to be effective in the treatment of AIDS although it has a shorter separation between the adenine and phosphorus than dideoxy-AMP and dAMP. By using pre-steady state kinetic methods, we examined the incorporation of the diphosphate of PMPA, 2',3'-dideoxyadenosine 5'-triphosphate (ddATP), and dATP catalyzed by wild-type human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, an exonuclease-deficient T7 DNA polymerase (T7 exo-), and wild-type rat DNA polymerase beta in order to evaluate the selectivity of PMPA as an antiviral inhibitor. With a DNA/DNA or DNA/RNA 22/43-mer duplex, the diphosphate of PMPA (PMPApp) is as effective as ddATP in reactions catalyzed by HIV-1 reverse transcriptase in that both analogs have similar substrate specificity constants (kp/Kd) which are only 5-fold lower than dATP. In contrast, PMPApp is a much weaker inhibitor of the reaction catalyzed by T7 exo- (with the DNA/DNA 22/43-mer duplex) in that PMPApp has a 5 x 10(-4)-fold lower kp/Kd than ddATP and dATP. The lower kp/Kd of PMPApp is due to a 1000-2000-fold lower incorporation rate (kp) and a 35-45-fold lower binding constant (Kd). Similarly, PMPApp is 800-fold less inhibitory toward polymerase beta with the DNA/DNA 22/43-mer duplex, whereas in studies with a single nucleotide gapped DNA (22-20/43-mer) PMPApp is 13-fold less inhibitory than ddATP. Although parallel studies will need to be performed using appropriate human polymerases, these results begin to define the mechanistic basis for the reported lower toxicity of PMPA in the treatment of AIDS.

Adenine↗
PubMed1998

DNA secondary structure effects on DNA synthesis catalyzed by HIV-1 reverse transcriptase.

The effect of DNA secondary structure on polymerization catalyzed by human immunodeficiency virus (HIV-1) reverse transcriptase (RT) was studied using a synthetic 66-nucleotide DNA template containing a stable hairpin structure. Four RT pause sites were identified within the first half of the hairpin stem. Additionally, five weak pause sites within the second half of the stem and the loop of the hairpin were identified at low temperatures. These weak pause sites were relocated to the site of the first few stem base pairs of two new hairpins formed due to a change in DNA secondary structure. Each pause site was correlated with a high free energy barrier of melting the stem base pair. Pre-steady state kinetic analysis of single nucleotide incorporation showed that polymerization at each pause site occurred by both a fast phase (10-20 s-1) and a slow phase (0. 02-0.07 s-1) during a single binding event. The reaction amplitudes of the fast phase were small (4-10% of enzyme sites), whereas the amplitudes of the slow phase were large (14-40%) at the pause sites. In contrast, only a single phase with a large reaction amplitude (32-50%) and a fast nucleotide incorporation rate (33-87 s-1) was observed at the non-pause sites. DNA substrates at all sites had similar dissociation rates (0.14-0.29 s-1) and overall binding affinity (16-86 nM). These results suggest that the DNA substrates at pause sites were bound in both productive and non-productive states at the polymerase site of RT. The non-productively bound DNA was slowly converted into a productive state upon melting of the next stem base pair without dissociation of the DNA from RT.

Base Pairing↗
PubMed1998

Alzheimer's beta-amyloid vasoactivity: identification of a novel beta-amyloid conformational intermediate.

The beta-amyloid (A beta) peptide has previously been shown to enhance phenylephrine or endothelin-1 induced constriction of aortic rings in vitro. The characteristics of A beta vasoactivity (dose, fragment length, timing) suggest that the mechanism is distinct from A beta cytotoxicity. To identify which properties of A beta determine its biological activity on vessels, we investigated a number of A beta analogues and fragments, individually and in combination, including those that are known to be associated with Alzheimer's disease (A beta(1-42)) and hereditary cerebral hemorrhage with amyloidosis--Dutch type (A beta(22Q)(1-40)). The vasoactivity appears to be related to the conformation adopted by the peptide in solution. The beta-pleated sheet rich A beta(1-42) and A beta(22Q)(1-40) were each less vasoactive than the mainly random coil wild type A beta(1-40). However, the most vasoactive A beta peptides were combinations which contain mixtures of random coil and beta-sheet structure. The finding that peptides containing low or high levels of beta-pleated conformation are less vasoactive than those containing intermediate amounts of this structural motif allows us to propose the existence of a transitional form between random coil and beta-pleated that is the vasoactive species of A beta. This is the first time that A beta conformational intermediates have been identified and a biological activity associated with them.

Amyloid beta-Peptides↗
PubMed1998

Alzheimer's beta-amyloid peptides induce inflammatory cascade in human vascular cells: the roles of cytokines and CD40.

Accumulating evidence suggests that beta-amyloid (Abeta)-induced inflammatory reactions may partially drive the pathogenesis of Alzheimer's disease (AD). Recent data also implicate similar inflammatory processes in cerebral amyloid angiopathy (CAA). To evaluate the roles of Abeta in the inflammatory processes in vascular tissues, we have tested the ability of Abeta to trigger inflammatory responses in cultured human vascular cells. We found that stimulation with Abeta dose-dependently increased the expression of CD40, and secretion of interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta) in endothelial cells. Abeta also induced expression of IFN-gamma receptor (IFN-gammaR) both in endothelial and smooth muscle cells. Characterization of the Abeta-induced inflammatory responses in the vascular cells showed that the ligation of CD40 further increased cytokine production and/or the expression of IFN-gammaR. Moreover, IL-1beta and IFN-gamma synergistically increased the Abeta-induced expression of CD40 and IFN-gammaR. We have recently found that Abeta induces expression of adhesion molecules, and that cytokine production and interaction of CD40-CD40 ligand (CD40L) further increase the Abeta-induced expression of adhesion molecules in these same cells. These results suggest that Abeta can function as an inflammatory stimulator to activate vascular cells and induces an auto-amplified inflammatory molecular cascade, through interactions among adhesion molecules, CD40-CD40L and cytokines. Additionally, Abeta1-42, the more pathologic form of Abeta, induces much stronger effects in endothelial cells than in smooth muscle cells, while the reverse is true for Abeta1-40. Collectively, these findings support the hypothesis that the Abeta-induced inflammatory responses in vascular cells may play a significant role in the pathogenesis of CAA and AD.

Alzheimer Disease↗
PubMed1998

The butyrylcholinesterase gene is neither independently nor synergistically associated with late-onset AD in clinic- and community-based populations.

The K variant of the butyrylcholinesterase gene (BChE) was recently found to occur at an increased frequency in a late onset Alzheimer's disease (AD) population, specifically in individuals carrying the epsilon4 allele of the apolipoprotein E (APOE) gene. This suggested synergy between these two genes resulting in an increased risk of late-onset AD. We have genotyped 62 community-based and 329 clinic-based AD cases, and 201 community-based controls at BChE and APOE and find no independent association between BChE and AD nor interaction with APOE in risk for AD in either our clinic or community-based samples.

Aged↗
PubMed1998

Characteristics of the in vitro vasoactivity of beta-amyloid peptides.

The beta-amyloid (A beta 1-40) peptide has previously been shown to enhance phenylephrine contraction of aortic rings in vitro. We have employed a novel observation, that A beta peptides enhance endothelin-1 (ET-1) contraction, to examine the relationship between vasoactivity and potential amyloidogenicity of A beta peptides, the role played by free radicals and calcium in the vasoactive mechanism, and the requirement of an intact endothelial layer for enhancement of vasoactivity. Rings of rat aortae were constricted with ET-1 before and after addition of amyloid peptide and/or other compounds, and a comparison was made between post- and pre-treatment contractions. In this system, vessel constriction is consistently dramatically enhanced by A beta 1-40, is enhanced less so by A beta 1-42, and is not enhanced by A beta 25-35. The endothelium is not required for A beta vasoactivity, and calcium channel blockers have a greater effect than antioxidants in blocking enhancement of vasoconstriction by A beta peptides. In contrast to A beta-induced cytotoxicity, A beta-induced vasoactivity is immediate, occurs in response to low doses of freshly solubilized peptide, and appears to be inversely related to the amyloidogenic potential of the A beta peptides. We conclude that the mechanism of A beta vasoactivity is distinct from that of A beta cytotoxicity. Although free radicals appear to modulate the vasoactive effects, the lack of requirement for endothelium suggests that loss of the free radical balance (between NO and O2-) may be a secondary influence on A beta enhancement of vasoconstriction. These effects of A beta on isolated vessels, and reported effects of A beta in cells of the vasculature, suggest that A beta-induced disruption of vascular tone may be a factor in the pathogenesis of cerebral amyloid angiopathy and Alzheimer's disease. Although the mechanism of enhanced vasoconstriction is unknown, it is reasonable to propose that in vivo contact of A beta peptides with small cerebral vessels may increase their tendency to constrict and oppose their tendency to relax. The subclinical ischemia resulting from this would be expected to up-regulate beta APP production in and around the vasculature with further increase in A beta formation and deposition. The disruptive and degenerative effects of such a cycle would lead to the complete destruction of cerebral vessels and consequently neuronal degeneration in the affected areas.

Alzheimer Disease↗