Chemical characterization of pro-inflammatory amyloid-beta peptides in human atherosclerotic lesions and platelets.

Amyloid-ß (Aß) peptides are intimately involved in the inflammatory pathology of atherosclerotic vascular disease (AVD) and Alzheimer's disease (AD). Although substantial amounts of these peptides are produced in the periphery, their role and significance to vascular disease outside the brain requires further investigation. Amyloid-ß peptides present in the walls of human aorta atherosclerotic lesions as well as activated and non-activated human platelets were isolated using sequential size-exclusion columns and HPLC reverse-phase methods. The Aß peptide isolates were quantified by ELISA and structurally analyzed using MALDI-TOF mass spectrometry procedures. Our experiments revealed that both aorta and platelets contained Aß peptides, predominately Aß40. The source of the Aß pool in aortic atherosclerosis lesions is probably the activated platelets and/or vascular wall cells expressing APP/PN2. Significant levels of Aß42 are present in the plasma, suggesting that this reservoir makes a minor contribution to atherosclerotic plaques. Our data reveal that although aortic atherosclerosis and AD cerebrovascular amyloidosis exhibit clearly divergent end-stage manifestations, both vascular diseases share some key pathophysiological promoting elements and pathways. Whether they happen to be deposited in vessels of the central nervous system or atherosclerotic plaques in the periphery, Aß peptides may promote and perhaps synergize chronic inflammatory processes which culminate in the degeneration, malfunction and ultimate destruction of arterial walls.

Is Alzheimer's disease amyloidosis the result of a repair mechanism gone astray?

Here, we synthesize several lines of evidence supporting the hypothesis that at least one function of amyloid-ß is to serve as a part of the acute response to brain hemodynamic disturbances intended to seal vascular leakage. Given the resilient and adhesive physicochemical properties of amyloid, an abluminal hemostatic repair system might be highly advantageous, if deployed on a limited and short-term basis, in young individuals. However, in the aged, inevitable cardiovascular dysfunction combined with brain microvascular lesions may yield global chronic hypoperfusion that may lead to continuous amyloid deposition and consequential negative effects on neuronal viability. A large body of experimental evidence supports the hypothesis of an amyloid-ß rescue function gone astray. Preventing or inducing the removal of amyloid in Alzheimer's disease (AD) has been simultaneously successful and disappointing. Amyloid deposits clearly play major roles in AD, but they may not represent the preeminent factor in dementia pathogenesis. Successful application of AD preventative approaches may hinge on an accurate and comprehensive view of comorbidities, including cardiovascular disease, diabetes, and head trauma.

Transcranial doppler ultrasound blood flow velocity and pulsatility index as systemic indicators for Alzheimer's disease.

BACKGROUND: Multiple lines of evidence suggest that cardiovascular co-morbidities hasten the onset of Alzheimer's disease (AD) or accelerate its course. METHODS: To evaluate the utility of cerebral vascular physical function and/or condition parameters as potential systemic indicators of AD, transcranial Doppler (TCD) ultrasound was used to assess cerebral blood flow and vascular resistance of the 16 arterial segments comprising the circle of Willis and its major tributaries. RESULTS: Our study showed that decreased arterial mean flow velocity and increased pulsatility index are associated with a clinical diagnosis of presumptive AD. Cerebral blood flow impairment shown by these parameters reflects the global hemodynamic and structural consequences of a multifaceted disease process yielding diffuse congestive microvascular pathology, increased arterial rigidity, and decreased arterial compliance, combined with putative age-associated cardiovascular output declines. CONCLUSIONS: TCD evaluation offers direct physical confirmation of brain perfusion impairment and might ultimately provide a convenient and a noninvasive means to assess the efficacy of medical interventions on cerebral blood flow or reveal incipient AD. In the near term, TCD-based direct assessments of brain perfusion might offer the prospect of preventing or mitigating AD simply by revealing patients who would benefit from interventions to improve circulatory system function.

Intracranial atherosclerosis as a contributing factor to Alzheimer's disease dementia.

BACKGROUND: A substantial body of evidence collected from epidemiologic, correlative, and experimental studies strongly associates atherosclerotic vascular disease (AVD) with Alzheimer's disease (AD). Depending on the precise interrelationship between AVD and AD, systematic application of interventions used to maintain vascular health and function as a component of standard AD therapy offers the prospect of mitigating the presently inexorable course of dementia. To assess this hypothesis, it is vital to rigorously establish the measures of AVD that are most strongly associated with an AD diagnosis. METHODS: A precise neuropathological diagnosis was established for all subjects, using a battery of genetic, clinical, and histological methods. The severity of atherosclerosis in the circle of Willis was quantified by direct digitized measurement of arterial occlusion in postmortem specimens and was compared between AD and nondemented control groups by calculating a corresponding index of occlusion. RESULTS: Atherosclerotic occlusion of the circle of Willis arteries was more extensive in the AD group than in the nondemented control group. Statistically significant differences were also observed between control and AD groups with regard to Braak stage, total plaque score, total neurofibrillary tangle score, total white matter rarefaction score, brain weight, Mini-Mental State Examination scores, and apolipoprotein E allelic frequencies. CONCLUSIONS: Our results, combined with a consideration of the multifaceted effects of impaired cerebral circulation, suggest an immediate need for prospective clinical trials to assess the efficacy of AD prevention using antiatherosclerotic agents.

Tg-SwDI transgenic mice exhibit novel alterations in AbetaPP processing, Abeta 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.

Patients with Alzheimer disease have altered transmitral flow: echocardiographic analysis of the vortex formation time.

OBJECTIVE: There is considerable epidemiologic evidence that Alzheimer disease (AD) is linked to cardiovascular risk factors and associated with an increased risk of symptomatic left ventricular (LV) dysfunction. Formation of a vortex alongside a diastolic jet signifies an efficient blood transport mechanism. The vortex formation time (VFT) is an index of optimal conditions for vortex formation. We hypothesized that AD and its associated cardiovascular risk factors impair diastolic transmitral flow efficiency and, therefore, shift the VFT value out of its optimal range. METHODS: Echocardiographic studies were performed on 45 participants in total: 22 patients with AD diagnosed according to the American Psychiatric Association's criteria and 23 age-matched individuals as a control group with cognitive function within normal limits. RESULTS: The echocardiographic ratio of the early to atrial phases of the LV filling velocities was significantly lower in the AD group (mean +/- SD, 0.67 +/- 14) when compared with the control individuals (0.79 +/- 0.14; P = .003). The interventricular septum diastolic thickness, left ventricular posterior wall diastolic thickness, and right ventricular end-diastolic diameter were significantly higher in the AD group (P

Amyloid precursor protein transgenic mouse models and Alzheimer's disease: understanding the paradigms, limitations, and contributions.

Transgenic (Tg) mice that overexpress mutant familial Alzheimer's disease (AD) amyloid precursor protein (APP) genes have contributed to an understanding of dementia pathology, and support the amyloid cascade hypothesis. Although many sophisticated mice APP models exist, none recapitulates AD cellular and behavioral pathology. The morphological resemblance to AD amyloidosis is impressive, but fundamental biophysical and biochemical properties of the APP/Abeta produced in Tg mice differ substantially from those of humans. The greater resilience of Tg mice in the presence of substantial Abeta burdens suggests that levels and forms deleterious to human neurons are not as noxious in these models. Transgenic mice were widely used for testing AD therapeutic agents, and demonstrated promising results. Unfortunately, clinical trials resulted in unforeseen adverse events or negative therapeutic outcomes. The disparity between success and failure is in part attributable to evolutionary divergence between humans and rodents. These observations suggest that the pathogenesis of AD is by far more intricate than can be explained by a straightforward accumulation of Abeta.

Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease.

BACKGROUND: We evaluated the amounts of amyloid beta (Abeta)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Abeta plasma levels and Alzheimer's disease (AD) pathology. METHODS: Amyloid beta levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects. RESULTS: Plasma Abeta levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Abeta40 than disease-free vessels. Inactivated platelets contained more Abeta peptides than activated ones. Substantially more Abeta was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Abeta. CONCLUSIONS: Efforts to use plasma levels of Abeta peptides as AD biomarkers or disease-staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Abeta values is also due in part to the ability of Abeta to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Abeta plasma levels. Furthermore, the long-range impact of Abeta immunotherapy on peripheral Abeta sources should also be considered.

APP/Aß structural diversity and Alzheimer's disease pathogenesis.

The amyloid cascade hypothesis of Alzheimer's disease (AD) proposes amyloid- ß (Aß) is a chief pathological element of dementia. AD therapies have targeted monomeric and oligomeric Aß 1-40 and 1-42 peptides. However, alternative APP proteolytic processing produces a complex roster of Aß species. In addition, Aß peptides are subject to extensive posttranslational modification (PTM). We propose that amplified production of some APP/Aß species, perhaps exacerbated by differential gene expression and reduced peptide degradation, creates a diverse spectrum of modified species which disrupt brain homeostasis and accelerate AD neurodegeneration. We surveyed the literature to catalog Aß PTM including species with isoAsp at positions 7 and 23 which may phenocopy the Tottori and Iowa Aß mutations that result in early onset AD. We speculate that accumulation of these alterations induce changes in secondary and tertiary structure of Aß that favor increased toxicity, and seeding and propagation in sporadic AD. Additionally, amyloid-ß peptides with a pyroglutamate modification at position 3 and oxidation of Met35 make up a substantial portion of sporadic AD amyloid deposits. The intrinsic physical properties of these species, including resistance to degradation, an enhanced aggregation rate, increased neurotoxicity, and association with behavioral deficits, suggest their emergence is linked to dementia. The generation of specific 3D-molecular conformations of Aß impart unique biophysical properties and a capacity to seed the prion-like global transmission of amyloid through the brain. The accumulation of rogue Aß ultimately contributes to the destruction of vascular walls, neurons and glial cells culminating in dementia. A systematic examination of Aß PTM and the analysis of the toxicity that they induced may help create essential biomarkers to more precisely stage AD pathology, design countermeasures and gauge the impacts of interventions.

RAGE and amyloid beta interactions: atomic force microscopy and molecular modeling.

In the AD brain, there are elevated amounts of soluble and insoluble Abeta peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble Abeta to soluble RAGE inhibits further aggregation of Abeta peptides, while membrane bound RAGE-Abeta interactions elicit activation of the NF-kappaB transcription factor promoting sustained chronic neuroinflammation. Atomic force microscopy observations demonstrated that the N-terminal domain of RAGE, by interacting with Abeta, is a powerful inhibitor of Abeta polymerization even at prolonged periods of incubation. Hence, the potential RAGE-Abeta structural interactions were further explored utilizing a series of computational chemistry algorithms. Our modeling suggests that a soluble dimeric RAGE assembly creates a positively charged well into which the negative charges of the N-terminal domain of dimeric Abeta dock.

Comparative proteomics of cerebrospinal fluid in neuropathologically-confirmed Alzheimer's disease and non-demented elderly subjects.

OBJECTIVES: Diagnostic tests able to reveal Alzheimer's disease (AD) in living patients before cognitive ability is destroyed are urgently needed. Such tests must distinguish AD from other dementia causes, as well as differentiate subtle changes associated with normal aging from true pathology emergence. A single biomarker offering such diagnostic and prognostic capacities has eluded identification. Therefore, a valuable test for AD is likely to be based on a specific pattern of change in a set of proteins, rather than a single protein. METHODS: We examined pooled cerebrospinal fluid (CSF) samples obtained from neuropathologically-confirmed AD (n=43) and non-demented control subjects (n=43) using 2-dimensional gel electrophoresis (2DE) proteomic methodology to detect differentially expressed proteins. Proteins exhibiting expression level differences between the pools were recovered and identified using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. RESULTS: Five differentially-expressed proteins with potential roles in amyloid-beta metabolism and vascular and brain physiology [apolipoprotein A-1 (Apo A-1), cathepsin D (CatD), hemopexin (HPX), transthyretin (TTR), and two pigment epithelium-derived factor (PEDF) isoforms] were identified. Apo A-1, CatD and TTR were significantly reduced in the AD pool sample, while HPX and the PEDF isoforms were increased in AD CSF. DISCUSSION: These results suggest that multi-factor proteomic pattern analysis of the CSF may provide a means to diagnose and assess AD.

Interaction of cardiovascular disease and neurodegeneration: transcranial Doppler ultrasonography and Alzheimer's disease.

OBJECTIVE: Recent post-mortem studies have reported that the severity of atheromatous deposits in the circle of Willis is significantly greater, relative to non-demented (ND) elderly persons, in subjects with neuropathologically diagnosed Alzheimer's disease (AD). Additionally, the severity of intracranial atherosclerosis correlates significantly with the densities of neuritic plaques and neurofibrillary tangles. In this study, we examine the arteries of the circle of Willis by transcranial Doppler (TCD) ultrasonography. METHODS: TCD was used to measure, in 25 AD patients and 30 ND elderly subjects, mean flow velocities and pulsatility indices in 16 different segments of the circle of Willis. The data were compared with and without adjustment for age, gender and systolic blood pressure. RESULTS: The AD patients had systematically higher pulsatility indices (p<0.005) than the ND group. Incremental increases of pulsatility indices in these segments had odds ratios ranging from 1.8 to 48 for the presence of AD when adjusted for age, gender and systolic blood pressure. The left internal carotid artery siphon and the left posterior cerebral artery were the two vessels that were strongly associated with AD diagnosis. Mean flow velocities were generally lower in patients with AD but the differences did not reach the significance level. DISCUSSION: The pulsatility indices of the arteries of AD patients were generally greater than those of similarly-aged ND subjects. This difference is most likely due to increased arterial wall rigidity imposed by atherosclerotic changes. Atherosclerotic disease of intracranial arteries may be a risk factor for AD.

Familial Presenilin Mutations and Sporadic Alzheimer's Disease Pathology: Is the Assumption of Biochemical Equivalence Justified?

Studies of presenilin (PSEN) gene mutations producing early onset Alzheimer's disease (AD) have helped elucidate the pathogenic mechanisms of dementia and guided clinical trials of potential therapeutic interventions. Although familial and sporadic forms of AD share features, it is unclear if the two are precisely equivalent. In addition, PSEN mutations do not all produce a single phenotype, but exhibit substantial variability in clinical manifestations, which are related to the position and chemical nature of their amino acid substitutions as well as ratios of critical molecules such as Aß40 and Aß42. These differences complicate the interpretation of critical clinical trial results and their desired extrapolation to sporadic AD treatment. In this perspective, we examine differences between familial AD and sporadic AD as well as attributes shared by these uniquely arising disturbances in brain biochemical homeostasis that culminate in dementia.

Chemical and neuropathological analyses of an Alzheimer's disease patient treated with solanezumab.

INTRODUCTION: Based on the amyloid cascade hypothesis of Alzheimer's disease (AD) pathogenesis, a series of clinical trials involving immunotherapies have been undertaken including infusion with the IgG1 monoclonal anti-Aß antibody solanezumab directed against the middle of the soluble Aß peptide. In this report, we give an account of the clinical history, psychometric testing, gross and microscopic neuropathology as well as immunochemical quantitation of soluble and insoluble Aß peptides and other proteins of interest related to AD pathophysiology in a patient treated with solanezumab. MATERIALS AND METHODS: The solanezumab-treated AD case (SOLA-AD) was compared to non-demented control (NDC, n = 5) and non-immunized AD (NI-AD, n = 5) subjects. Brain sections were stained with H&E, Thioflavine-S, Campbell-Switzer and Gallyas methods. ELISA and Western blots were used for quantification of proteins of interest. RESULTS: The SOLA-AD subject's neuropathology and biochemistry differed sharply from the NDC and NI-AD groups. The SOLA-AD case had copious numbers of amyloid laden blood vessels in all areas of the cerebral cortex, from leptomeningeal perforating arteries to arteriolar deposits which attained the cerebral amyloid angiopathy (CAA) maximum score of 12. In contrast, the maximum CAA for the NI-AD cases averaged a total of 3.6, while the NDC cases only reached 0.75. The SOLA-AD subject had 4.4-fold more soluble Aß40 and 5.6-fold more insoluble Aß40 in the frontal lobe compared to NI-AD cases. In the temporal lobe of the SOLA-AD case, the soluble Aß40 was 80-fold increased, and the insoluble Aß40 was 13-fold more abundant compared to the non-immunized AD cases. Both soluble and insoluble Aß42 levels were not dramatically different between the SOLA-AD and NI-AD cohort. DISCUSSION: Solanezumab immunotherapy provided no apparent relief in the clinical evolution of dementia in this particular AD patient, since there was a continuous cognitive deterioration and full expression of amyloid deposition and neuropathology.

Circle of willis atherosclerosis is a risk factor for sporadic Alzheimer's disease.

OBJECTIVE: We conducted a quantitative investigation of brain arterial atherosclerotic damage and its relationship to sporadic Alzheimer's disease (AD). METHODS AND RESULTS: Fifty-four consecutive autopsy cases, 32 AD and 22 nondemented control subjects, were examined to establish the degree of arterial stenosis. Vessel external and lumenal area measurements were taken from 3-mm arterial cross-sections to calculate a stenosis index. AD patient circle of Willis arteries possessed a significant degree of stenosis as a consequence of multiple and severe atherosclerotic lesions. These lesions were significantly more severe in AD cases than in age-matched controls (P<0.0001), and the number of stenoses and the index of occlusion (R=0.67; P<0.00001) were positively correlated. In addition, the index of stenosis significantly correlated with the following measures of AD neuropathological lesions: total plaque score, neuritic plaque score, neurofibrillary tangle score, Braak stage score, and white matter rarefaction score. CONCLUSIONS: Our study reveals an association between severe circle of Willis atherosclerosis and sporadic AD that should be considered a risk factor for this dementia. These observations strongly suggest that atherosclerosis-induced brain hypoperfusion contributes to the clinical and pathological manifestations of AD.

Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease.

Extracellular fibrillar amyloid deposits are prominent and universal Alzheimer's disease (AD) features, but senile plaque abundance does not always correlate directly with the degree of dementia exhibited by AD patients. The mechanism(s) and dynamics of Abeta fibril genesis and deposition remain obscure. Enhanced Abeta synthesis rates coupled with decreased degradative enzyme production and accumulating physical modifications that dampen proteolysis may all enhance amyloid deposit formation. Amyloid accumulation may indirectly exert the greatest pathologic effect on the brain vasculature by destroying smooth muscle cells and creating a cascade of negative impacts on cerebral blood flow. The most visible manifestation of amyloid dis-equilibrium could actually be a defense mechanism employed to avoid serious vascular wall degradation while the major toxic effects to the gray and white matter neurons are mediated by soluble oligomeric Abeta peptides with high beta-sheet content. The recognition that dynamic soluble oligomeric Abeta pools exist in AD and are correlated to disease severity led to neurotoxicity and physical conformation studies. It is now recognized that the most basic soluble Abeta peptides are stable dimers with hydrophobic regions sequestered from the aqueous environment and are capable of higher order aggregations. Time course experiments employing a modified ELISA method able to detect Abeta oligomers revealed dynamic intermolecular interactions and additional experiments physically confirmed the presence of stable amyloid multimers. Amyloid peptides that are rich in beta-sheet structure are capable of creating toxic membrane ion channels and a capacity to self-assemble as annular structures was confirmed in vitro using atomic force microscopy. Biochemical studies have established that soluble Abeta peptides perturb metabolic processes, provoke release of deleterious reactive compounds, reduce blood flow, induce mitochondrial apoptotic toxicity and inhibit angiogenesis. While there is no question that gross amyloid deposition does contribute to AD pathology, the destructive potential now associated with soluble Abeta suggests that treatment strategies that target these molecules may be efficacious in preventing some of the devastating effects of AD.

The effects of salt concentration and growth phase on MRSA solar and germicidal ultraviolet radiation resistance.

The extensive use of antimicrobial drugs has led to the widespread emergence of resistant bacterial strains. One such organism, methicillin-resistant Staphylococcus aureus, is now found extensively in both healthcare facilities and diverse community settings such as households, correctional facilities, and athletic teams. The importance of ultraviolet radiation as an adjunctive therapy to reduce bioburden and improve wound status in patients has been documented. An in vitro study to assess the effects of different types of ultraviolet radiation on antibiotic-resistant strains was conducted to provide information that will aid in the development of rational UV irradiation medical protocols. Methicillin-resistant Staphylococcus aureus was found to be sensitive to both germicidal (ultraviolet C) and solar (ultraviolet A and B) ultraviolet radiation (ultraviolet C substantially more lethal). For both types of ultraviolet radiation, as the medium concentration of sodium chloride increased, the methicillin-resistant Staphylococcus aureus cells exhibited increased sensitivity. It also was shown for both types of ultraviolet radiation that kill curves were comparable for log and stationary phase methicillin-resistant Staphylococcus aureus cells. Photoreactivation was observed for Pseudomonas aeruginosa PAO-1 but not for methicillin-resistant Staphylococcus aureus when ultraviolet C was applied to log phase cells. The Gram-negative Pseudomonas aeruginosa PAO-1 was considerably more sensitive than the Gram-positive methicillin-resistant Staphylococcus aureus to ultraviolet C radiation. The experiments reveal that medium composition exerts a substantial effect on methicillin-resistant Staphylococcus aureus ultraviolet resistance and that this species lacks photoreactivation capacity. This suggests that in a clinical setting, eradication of the bacterium may be achieved at far lower doses of ultraviolet radiation than would be indicated by treatment protocols that do not account for ionic conditions.

Atherosclerosis of cerebral arteries in Alzheimer disease.

A growing body of evidence suggests that vascular disease underlies Alzheimer dementia. Atherosclerotic lesions in the circle of Willis and large leptomeningeal vessels were quantified and found to correlate with Alzheimer disease (AD) clinical diagnosis and neuropathology. We hypothesize that AD pathology is the complex end result of slowly evolving vascular disease and parenchymal lesions. Confirmation of a central role for vascular pathology in AD will suggest important treatment options and directions for additional interventions to stave off this dementia.

A beta, aging, and Alzheimer's disease: a tale, models, and hypotheses.

In this paper we explore the potential functional role of the A beta peptides in the context of Alzheimer's disease (AD). We begin by defining the morphology of the amyloid deposits in relation to surrounding glial cells and, more importantly, in relation to the brain vasculature. Amyloid accumulation in the brain's microvasculature causes disturbances in the blood-brain barrier (BBB), and in larger arteries, impairment in control of regional cerebral blood flow due to myocyte degeneration. We postulate that the deposition of vascular amyloid may represent a hydrophobic protein plaster to seal leaks in the BBB, occasionally observed in aging and catastrophically common in AD. The vasoconstrictive activity of A beta may also be related to leaky vessels whereby decreasing the arterial diameter may also help to control breaches in the BBB. The admission of plasma neurotoxic proteins into the brain may be controlled by activation of microglia elicited by soluble A beta peptides creating a subtle, but permanent brain inflammatory reaction. We also delve into the influence that cholesterol metabolism may have in membrane topology and A beta production, and the close correlations that exist between cardiovascular disease and AD. Finally, we speculate about the possibility of a peripheral source of A beta that may, by crossing the BBB, contribute to the vascular and parenchymal deposits of A beta in the AD brain.