Amyloid Material Research Articles

Choroid plexus papilloma with stromal deposition of amyloid and elastic material

Congophilic birefringent amyloid deposits, with immunostaining for transthyretin (TTR) and amyloid P, associated with numerous coarse, enlarged and thick elastic fibres, are reported in the stroma of two choroid plexus papillomas, a finding not previously described in choroid plexus tumours. TTR was expressed as aggregates of ‘doughnut-shaped’ bodies, in which the TTR-positive peripheral area encircled the elastic fibre (TTR-negative core). Ultrastructurally, the amyloid microfibrils surrounded the elastic fibres and appeared to continue into the microfibrillar mantle of the latter. The stromal TTR-amyloid deposits associated with abundant elastic fibres in tumours that occur in the choroid plexus may be related to the alteration (production/accumulation, insufficient breakdown and/or extracellular matrix modifications) of some of the choroid plexus functions (removal, target and source of polypeptides, including TTR synthesis) and may be of interest for future studies on choroid plexus polypeptide activity and on protein development into elastomeric and amyloidogenic microfibrils.

The molecular skin pathology of familial primary localized cutaneous amyloidosis

Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal dominant disorder associated with chronic itching and skin lichenification. In lesional skin, there are apoptotic basal keratinocytes and deposits of amyloid material on degenerate keratin filaments in the upper dermis. The genetic basis of FPLCA involves mutations in the OSMR and IL31RA genes but the disease pathophysiology is not fully understood. In this study, we identified new pathogenic heterozygous missense mutations in the OSMR gene (p.Val631Leu and p.Asp647Tyr) in two Dutch FPLCA families. We then compared gene expression profiles between FPLCA lesional skin (n = 4) and site-matched control skin (n = 6). There was twofold or greater upregulation of 34 genes and downregulation of 43 genes. Most changes in gene expression (verified by quantitative RT-PCR) reflected alterations in epidermal differentiation and proliferation consistent with lichenification, but we also noted a reduction in several interfollicular keratinocyte stem cell markers in FPLCA skin. Differences in gene expression were also noted for proteins involved in apoptosis and nerve conduction. Collectively, this study expands the molecular basis of FPLCA and provides new insight into the skin pathology of this condition.

Anatomia patológica da sinóvia de pacientes submetidos à liberação do túnel do carpo

OBJETIVO: Verificar se a biópsia da sinóvia do túnel do carpo é capaz de identificar patologias sistêmicas que não foram diagnosticadas clinicamente ou por exames laboratoriais. MÉTODO: 46 exames anatomopatológicos da sinóvia dos tendões flexores no túnel do carpo de pacientes submetidos à liberação aberta para o tratamento desta síndrome compressiva foram, retrospectivamente, analisados. Os autores propuseram uma nova classificação para a lesão de acordo com a intensidade do processo inflamatório. RESULTADOS: O exame anatomopatológico mostrou que 56,6% das lâminas foram classificadas como grau I (sem alterações inflamatórias), 32,6%, grau II (infiltrado leucocitário e fibrose discretos, além de hialinose), 4,3%, grau III (infiltrado leucocitário e fibrose intensos, presença de fibrina e neoformação vascular) e 6,5%, grau IV (as alterações acima descritas associadas à presença de calcificação local e células gigantes). Dois pacientes com amiloidose foram classificados como graus I e II e não foram encontrados depósitos de material amilóide em suas lâminas. Dois pacientes portadores de hiperparatireoidismo e outro com insuficiência renal crônica foram classificados como grau IV. CONCLUSÃO: A realização da biópsia da sinóvia do túnel do carpo, além de agregar custos adicionais ao procedimento, não possibilitou o diagnóstico precoce de doenças sistêmicas em pacientes portadores de síndrome do túnel do carpo.

A Case of Amyloid Goiter Associated with Intrathyroid Parathyroid and Lymphoepithelial Cyst

Diffuse enlargement of the thyroid gland accompanied by an interstitial tissue deposition of amyloid is a special entity termed an amyloid goiter. An amyloid goiter is a rare thyroid lesion, which has been described a long time ago. In this report, we add a new classic case of amyloid goiter that differs from other reported cases in its association with intrathyroid parathyroid and lymphoepthelial cyst involved with amyloidosis. The presence of parathyroid tissue inside the thyroid parenchyma and surrounded by amyloid material elicited a diagnostic problem due to suspected medullary carcinoma. Careful histological examination and immunohistochemical staining for parathormone and calcitonin have largely helped in the differential diagnosis. Bilaterality, diffuse, and homogeneous involvement of the thyroid gland, with absence of definite masses, all direct the diagnosis toward amyloid goiter.

Differences and similarities between CADASIL and other small vessel diseases of the brain

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited non-amyloid and non-arteriosclerotic vessel disease. The defective gene is Notch3 at chromosome 19. Similarly to cerebral small vessel disease (SVD), comprising small vessel atherosclerosis, lipohyalinosis (firbrinoid necrosis), and arteriolosclerosis, it mainly affects penetrating small and medium-sized arteries of the white matter. Contrasting SVD and similarly to cerebral amyloid angiopathy (CAA) it is also present in leptomeningeal blood vessels. Microscopic changes in CADASIL include thickening of the vessel walls. The background is a degenerating tunica media with deposition of granular material. The thickening of the arterial wall is mainly due to accumulation of extracellular matrix proteins including various types of collagen and laminin. This granular material distinguishes CADASIL from the fibrotic thickening of arteriolosclerosis (Binswanger disease) and amyloid accumulation in CAA. It is also different from lipohyalinosis that shows architectural disorganization, mural foam cells, and fibrinoid degeneration. The major pathogenetic feature of CADASIL is destruction of vascular smooth muscle cells. In lipohyalinosis (fibrinoid necrosis) type of SVD blood brain barrier breakdown, plasma protein leak and deposition, smooth muscle and elastic lamina degeneration, and fibrinoid necrosis may be observed. In CAA production of amyloid material by smooth muscle cells, pericytes, or endothelial cells, and/or altered drainage pathways is considered. Major consequences of CADASIL include lacunar infarctions and vascular leukoencephalopathy leading to dementia similarly to arteriolosclerotic type of SVD (Binswanger). In contrast, in lipohyalinosis (fibrinoid necrosis) type of SVD and CAA hemorrhagic complications may also occur.

Plasmacytoma with amyloidosis masquerding as tuberculosis on cytology

Amyloid material on lymph node cytology smears can mimic caseous necrosis. We report one such case where a 50-year-old lady presented with a nasal mass and cervical lymphadenopathy. Fine needle aspiration cytology smears of the cervical lymph node were interpreted as tuberculous lymphadenitis based on the presence of an occasional epithelioid cell and caseous material. The patient did not respond to antituberculous therapy and was revaluated. Repeat aspiration from the lymph node showed numerous plasma cells and myeloma cells in addition to the amorphous material which was confirmed to be amyloid on staining with congo red. A diagnosis of plasmacytoma with amyloidosis was rendered. Imprint smears from nasal mass, detailed hematology workup and subsequent histology confirmed the diagnosis.

Solitary Amyloid Tumor of the Tongue Base

The purpose of this article is to present a rare case of localized, solitary amyloid tumor of tongue base and emphasize some of the characteristic features of challenging clinical and histopathologic diagnosis. In this paper, we focused on the clinical and pathological specifications of this rare tumor, so any unnecessary examinations or measures may be spared. Negative staining of amyloid material with AAC and osseous metaplasia noted in the histopathologic examination may not be thought as definite criteria for localized amyloidosis, but a supporter of localized, solitary amyloid tumor diagnosis.

On the association between amyloid fibrils and glycosaminoglycans; possible interactive role of Ca2+ and amyloid P-component.

We have previously reported the specific association of glycosaminoglycans (GAG) and proteoglycans (PG) with amyloid fibrils and characterized the polysaccharides directly extracted from amyloid-laden tissues. In the present study we further elucidate the association between purified amyloid fibrils and GAG/PG with special reference to those GAG/PG associated with amyloid P-component (AP) and the interactive role of Ca2+ ions. Amyloid fibrils were isolated from human hepatic AA amyloid employing water extraction with and without preceding removal of AP, an extrafibrillar protein component of all amyloids, using sodium citrate. GAG/PG co-isolated with the amyloid extracts, with and without AP, were isolated and characterized. Agarose-affinity chromatography of extracts containing AP was performed, and the GAG associated with this extrafibrillary protein were characterized as well. Several different GAG/PG populations were demonstrated in the various extracts. The abolition of calcium-dependent binding markedly influenced the amount of GAG/PG recovered in the fibril extracts, as well as the total amount of amyloid material obtained. Thus, it seems that calcium plays an important role in the association between the fibrils and the sugar moieties, and that a significant fraction of the GAG found in amyloid exhibits a Ca(2+)-dependent fibril-GAG interaction. No significant difference in the proportion between galactosaminoglycans and glucosamines was, however, disclosed when the two extraction protocols were compared, suggesting that no particular GAG species has a higher affinity for the fibrils themselves. Both dermatan/chondroitin sulphate and heparan sulphate identified in the present study exhibited a Ca(2+)-dependent interaction with AP, supporting previous findings. However, the amyloid-associated galactosaminoglycans found, especially the large PG appearing in small amounts, seemed to have a higher affinity for the extrafibrillar AP than the other GAG.

Solitary amyloid tumor of the breast

Primary breast amyloidosis is uncommon and the solitary amyloid tumor of the breast is rarely mentioned in literature. We report the clinical history of a woman presenting with mammograms an area of clustered microcalcifications, with irregular and pleomorphic morphology, mimicking the onset of a cancer. The core biopsy specimens resulting in breast amyloidosis were in disagreement with the radiological Breast Imaging Reporting and Data System (BI-RADS) risk, category 4. Moreover, specimens from abdominal subcutaneous fat and bone marrow biopsies showed no evidence of deposition of amyloid material, allowing exclusion of a systemic disease. Because it is reported the frequent association between breast amyloidosis and malignant lesions, a surgical excision of the microcalcifications was performed. Final histology confirmed the benign nature of the lesion consisting in a solitary amyloid tumor of the breast. This case stresses the importance of multidisciplinary collaboration between Radiologists, Surgeons and Pathologists to achieve a correct diagnosis and treatment of this rare breast disease.

Macular Involvement in Secondary Systemic Amyloidosis

A patient with subretinal and preretinal hemorrhage after secondary systemic amyloidosis due to familial Mediterranean fever is presented. Case presentation. A 30-year-old woman with secondary systemic amyloidosis secondary to familial Mediterranean fever presented with painless visual loss in the right eye. The examination demonstrated multiple subretinal and preretinal hemorrhages, massive deposits which may represent amyloid material at the left macular region. After 6 months, the hemorrhages disappeared, but deposits persisted. The macular deposition and hemorrhage is an uncommon manifestation of secondary systemic amyloidosis secondary to familial Mediterranean fever. Further evidence is necessary to understand the nature of these deposits and their relevance to secondary systemic amyloidosis and/or familial Mediterranean fever.

New Strategy for the Generation of Specific d-Peptide Amyloid Inhibitors

The conversion of a soluble protein into β-sheet-rich oligomeric structures and further fiber formation are critical steps in the pathogenesis of the group of human diseases known as amyloidoses. Drugs that interfere with this process may thus be able to prevent and/or cure these diseases. Recent results have shown that short amino acid stretches can provide most of the driving force needed to trigger amyloid formation of a protein. These evidence suggest that compounds that specifically bind to peptides synthesized upon the sequence of such amyloidogenic protein stretches might also be able to inhibit amyloid formation of the corresponding full-length protein and, likely, amyloid-induced cytotoxicity as well. Here we present a general strategy to obtain d-peptides that specifically interact with protein amyloid stretches. The screening of a d-peptide combinatorial library for inhibitors of an amyloidogenic peptide designed de novo has allowed us to extract a set of empirical rules for the design of d-peptide inhibitors of any six-residue amyloidogenic stretch. d-peptides generated on these bases prevent amyloid formation and disassemble preformed fibrils of different amyloid hexapeptides identified in human amyloid proteins. In addition, they are also specific for their target sequence. The d-peptide designed here for the Alzheimer's Aβ 1–42 peptide not only inhibits and disassembles amyloid material but also reduces Aβ 1–42 amyloid-induced cytotoxicity in cell culture.

Formation of a High Affinity Lipid-Binding Intermediate during the Early Aggregation Phase of α-Synuclein

The alpha-synuclein (alpha-syn) protein is clearly implicated in Parkinson's disease (PD). Mutations or triplication of the alpha-syn gene leads to early onset PD, possibly by accelerating alpha-syn oligomerization. alpha-syn interacts with lipids, and this membrane binding activity may relate to its toxic activity. To understand how the alpha-syn aggregation state affects its lipid binding activity we used surface plasmon resonance to study the interaction of wild-type and mutant alpha-syn with a charged phospholipid membrane, as a function of its aggregation state. Apparent dissociation constants for alpha-syn indicated that an intermediate species, present during the lag phase of amyloid formation, binds with an increased affinity to the membrane surface. Formation of this species was dependent upon the rate of fibril formation. Fluorescence anisotropy studies indicate that only upon the formation of amyloid material can alpha-syn perturb the acyl-chain region of the lipid bilayer. Circular dichroism spectroscopy showed that upon aging, both wild-type and mutant alpha-syn lose their ability to form lipid-bound alpha-helical species once they become fibrillar. These results indicate that alpha-syn forms a high affinity lipid binding intermediate species during fibril formation. Oligomeric alpha-syn is known to be toxic, and it is feasible that the high affinity binding species described here may correspond to a toxic species involved in PD.

Oncostatin M Receptor-β Mutations Underlie Familial Primary Localized Cutaneous Amyloidosis

Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMRbeta), in three families. OSMRbeta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching.

Amyloidosis Presenting with Platelet Dysfunction and Recurrent Retroperitoneal Hemorrhage (RH).

CASE REPORT: A 59-year-old white female with history of easy bruising for 2 years and 2 episode of RH in the last 6 month admitted to ICU with her 3rd episode of RH. Her previous w/o included a BM Bx which had shown clonal population of plasma cells kappa chain restrictive (7%) with repeatedly negative SPEP and UPEP. PFA-100 was consistent with severe platelet dysfunction. During the ICU admission platelet transfusion with multiple single donor units did not correct her PFA-100 results, which were confirmed with platelet aggregation results. Both, collagen/epinephrine and collagen/ADP closure times were prolonged (>300 and 128 seconds respectively). The patient however did not receive any medications to explain this apparently intrinsic dysfunction. Coagulation studies including PT, aPTT and factor II, VII, VIII, IX all were within normal limit. Factor X levels were slightly decreased (45%). Patient had selective embolization of the fourth lobar artery of the right kidney. Plasma cells in the marrow showed monoclonal expression for cytoplasmic kappa light chains by both IHC and in situ hybridization. Amorphous pink material was present in the walls of blood vessels. Plasma cells stained positively with CD138. The amyloid material stained positively with Congo red and demonstrated apple green birefringence under polarized light. Skeletal survey demonstrated multiple lytic lesions. Serum free light chain measurement showed high levels of M protein (κ) with κ to λ ration of 4.30. Patient was started on treatment with pulse dose steroid and bortezomib.DISCUSSION: Amyloidosis can cause hemorrhage with multiple mechanisms including amyloid deposition (amyloid angiopathy), platelet dysfunction, coagulation factor deficiencies, abnormal fibrin polymerization and hyperfibrinolysis. Consumption of factor X by amyloid is often called a culprit for hemorrhage in amyloidosis. The slightly decreased level of factor X in this case provided a valuable clue for diagnosis, but was not likely a cause of bleeding in this patient. Amyloid induced platelet dysfunction along with amyloid angiopathy lead to life threatening hemorrhage in our patient. The mechanism of this platelet dysfunction, which also affected the transfused platelets, is not well explained. This effect on platelets complicates the clinical management. The case also illustrates the value of the free light chain assay, which is more sensitive than SPEP and UPEP. These commonly used tests to diagnose plasma cell dyscrasias are reportedly false negative in 3% of cases.CONCLUSION: Plasma cell dyscrasia has a wide variety of presentation and should be considered as a part of bleeding work up in complex cases.

532‐nm and 1064‐nm Q‐switched Nd:YAG laser therapy for reduction of pigmentation in macular amyloidosis patches

Macular amyloidosis is a primary form of skin amyloidosis with deposition of small to moderate amyloid material in the upper dermis and mild pigmentary incontinence with resultant clinical hyperpigmentation. To determine the efficiency of Q-switched Nd:YAG laser (532 and 1064 nm) in reducing the pigmentations due to skin macular amyloidosis. A prospective, side by side, controlled, clinical trial study was designed. Twenty subjects with clinical diagnosis and pathology confirmation of macular amyloidosis were treated with Q-switched Nd:YAG laser: 532 nm in a part of their plaques and with 1064 nm in another part of their plaques. Assessment of efficiency was done by colorimetric scores based on Mexameter measurement and also digital photographs before laser therapy and 8 weeks after treatment. Mexameter-based data analysis showed that the two lasers (Q-switched 532 and 1064 Nd:YAG) are effective in reducing the degree of macular amyloidosis patches pigmentation, and 532 nm is meaningfully more effective than 1064 nm in this matter. Photograph-based analysis showed that 90% of cases treated by 532 nm had good or very good response, and for the 1064 nm-treated patches, 60% of cases had the good or very good response. The results of study showed the net positive effect of Q-switched Nd:YAG laser, either 532 nm or 1064 nm, in pigment reduction of macular amyloidosis patches, but the 532-nm laser was more effective than 1064 laser.

Concentration Dependent Cu2+Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

The Amyloid beta peptide (Abeta) of Alzheimer's diseases (AD) is closely linked to the progressive cognitive decline associated with the disease. Cu2+ ions can induce the de novo aggregation of the Abeta peptide into non-amyloidogenic aggregates and the production of a toxic species. The mechanism by which Cu2+ mediates the change from amyloid material toward Cu2+ induced aggregates is poorly defined. Here we demonstrate that the aggregation state of Abeta1-42 at neutral pH is governed by the Cu2+:peptide molar ratio. By probing amyloid content and total aggregation, we observed a distinct Cu2+ switching effect centered at equimolar Cu2+:peptide ratios. At sub-equimolar Cu2+:peptide molar ratios, Abeta1-42 forms thioflavin-T reactive amyloid; conversely, at supra-equimolar Cu2+:peptide molar ratios, Abeta1-42 forms both small spherical oligomers approximately 10-20 nm in size and large amorphous aggregates. We demonstrate that these insoluble aggregates form spontaneously via a soluble species without the presence of an observable lag phase. In seeding experiments, the Cu2+ induced aggregates were unable to influence fibril formation or convert into fibrillar material. Aged Cu2+ induced aggregates are toxic when compared to Abeta1-42 aged in the absence of Cu2+. Importantly, the formation of dityrosine crosslinked Abeta, by the oxidative modification of the peptide, only occurs at equimolar molar ratios and above. The formation of dityrosine adducts occurs following the initiation of aggregation and hence does not drive the formation of the Cu2+ induced aggregates. These results define the role Cu2+ plays in modulating the aggregation state and toxicity of Abeta1-42.

Amyloid-β 1–42 induced endocytosis and clusterin/apoJ protein accumulation in cultured human astrocytes

Recent studies indicate that astrocytes may be the primary target of secreted amyloid-β 1–42 peptides, with the neurotoxicity representing a secondary response to astrocytic stress. Our purpose was to clarify the astrocytic stress response induced by amyloid-β peptides in human and rat astrocytes. Human amyloid-β 1–42 peptides and fibrils induced the appearance of cytoplasmic vacuoles in normal human astrocytes (NHA) and CCFsttg1 astrocytoma cells. Vacuoles appeared 9–12 h after the amyloid-β exposure and remained present for several days. Rat primary neonatal astrocytes showed similar but less prominent vacuolar response. Human amyloid-β peptides 1–16, 1–28, 10–20, 17–21 and 25–35 did not cause vacuole formation. Electron microscopic observations revealed large endocytic vacuoles containing fibrillar amyloid material. Stress marker analysis did not show any increase in protein levels of HSP70, HSP90, GRP78 and GRP94. However, the protein level of clusterin/apoJ, a secreted chaperone, was strongly increased both in NHA and CCFsttg1 astrocytes. Endocytic response associated with the accumulation of clusterin/apoJ protein suggests that clusterin/apoJ has a role in the clearance of amyloid-β peptides.

Occurrence and co-localization of amyloid β-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice

The deposition of the amyloid β-protein (Aβ) is a hallmark of Alzheimer's disease (AD). One reason for Aβ-accumulation and deposition in the brain may be an altered drainage along perivascular channels. Extracellular fluid is drained from the brain towards the cervical lymph nodes via perivascular channels. The perivascular space around cerebral arteries is the morphological correlative of these drainage channels. Here, we show that Aβ is immunohistochemically detectable within the perivascular space of 25 months old wild-type and amyloid precursor protein (APP)-transgenic mice harboring the Swedish double mutation driven by a neuron specific promoter. Only small amounts of Aβ can be detected immunohistochemically in the perivascular space of wild-type mice. Cerebrovascular and parenchymal Aβ-deposits were absent. In APP-transgenic mice, large amounts of Aβ were found in the perivascular drainage channels accompanied with cerebrovascular and parenchymal Aβ-deposition. The apolipoprotein E (apoE) immunostaining within the perivascular channels did not vary between wild-type and APP-transgenic mice. Almost 100% of the area that represents the perivascular space was stained with an antibody directed against apoE. Here, Aβ co-localized with apoE indicating an involvement of apoE in the perivascular clearance of Aβ. Fibrillar congophilic amyloid was not seen in wild-type mice. In APP-transgenic animals, congophilic fibrillar amyloid material was seen in the wall of cerebral blood vessels but not in the perivascular space. In conclusion, our results suggest that non-fibrillar forms of Aβ are drained along perivascular channels and that apoE is presumably involved in this clearance mechanism. Overloading such a clearance mechanism in APP-transgenic mice appears to result in insufficient Aβ-clearance, increased Aβ-levels in the brain and the perivascular drainage channels, and finally in Aβ-deposition. In so doing, our results strengthen the hypothesis that an alteration of perivascular drainage supports Aβ-deposition and the development of AD.

Collagen Plays an Active Role in the Aggregation of β2-Microglobulin under Physiopathological Conditions of Dialysis-related Amyloidosis

Dialysis-related amyloidosis is characterized by the deposition of insoluble fibrils of beta(2)-microglobulin (beta(2)-m) in the musculoskeletal system. Atomic force microscopy inspection of ex vivo amyloid material reveals the presence of bundles of fibrils often associated to collagen fibrils. Aggregation experiments were undertaken in vitro with the aim of reproducing the physiopathological fibrillation process. To this purpose, atomic force microscopy, fluorescence techniques, and NMR were employed. We found that in temperature and pH conditions similar to those occurring in periarticular tissues in the presence of flogistic processes, beta(2)-m fibrillogenesis takes place in the presence of fibrillar collagen, whereas no fibrils are obtained without collagen. Moreover, the morphology of beta(2)-m fibrils obtained in vitro in the presence of collagen is extremely similar to that observed in the ex vivo sample. This result indicates that collagen plays a crucial role in beta(2)-m amyloid deposition under physiopathological conditions and suggests an explanation for the strict specificity of dialysis-related amyloidosis for the tissues of the skeletal system. We hypothesize that positively charged regions along the collagen fiber could play a direct role in beta(2)-m fibrillogenesis. This hypothesis is sustained by aggregation experiments performed by replacing collagen with a poly-L-lysine-coated mica surface. As shown by NMR measurements, no similar process occurs when poly-L-lysine is dissolved in solution with beta(2)-m. Overall, the findings are consistent with the estimates resulting from a simplified collagen model whereby electrostatic effects can lead to high local concentrations of oppositely charged species, such as beta(2)-m, that decay on moving away from the fiber surface.

Plaques of Alzheimer’s disease originate from cysts of Borrelia burgdorferi, the Lyme disease spirochete

Here is hypothesized a truly revolutionary notion that rounded cystic forms of Borrelia burgdorferi are the root cause of the rounded structures called plaques in the Alzheimer brain. Rounded "plaques' in high density in brain tissue are emblematic of Alzheimer's disease (AD). Plaques may be conceptualized as rounded "pock mark-like" areas of brain tissue injury. In this century, in brain tissue of AD, plaques are Amyloid Plaques according to the most up to date textbooks. In the last century, however, Dr. Alois Alzheimer did not require amyloid as the pathogenesis for either the disease or for the origin of its plaques. Surely, amyloid is an event in AD, but it may not be the primal cause of AD. Indeed in plaques, amyloid is regularly represented by the "congophilic core" structure which is so named because the waxy amyloid material binds the congo red stain and is congophilic. However an accepted subset of plaques in AD is devoid of a congophilic amyloid core region (these plaques "cotton wool" type plaques, lack a central congophilic core structure). Furthermore, there is "plaque diversity" in Alzheimer's; small, medium and large plaques parallel variable cystic diameters for Borrelia burgdorferi. Perturbations of AD plaque structure (i.e. young plaques devoid of a central core and older plaques with or without a central core structure) offer room for an alternate pathway for explanation of ontogeny of the plaque structures. If amyloid is not required to initiate all of the possible plaques in Alzheimer's, is it possible that amyloid just a by product of a more fundamental primal path to dementia? If a byproduct status is assigned to amyloid in the realm of plaque formation, then is amyloid also an epiphenomenon rather than a primary pathogenesis for Alzheimer's disease. In the "anatomy is destiny" model, cysts of borrelia are always round. Why then not accept roundness as a fundamental "structure determines function" argument for the answer to the mystery of why Alzheimer plaques are always round? Parataxis causality, a concept borrowed from philosophy, is the error that comes from linking two events, which occur contemporaneously or in close proximity to one another with a cause and effect relationship. Parataxis tells us that what appears to be cause and effect in the couplet "amyloid plaque" merely by a proximity relationship may be "spurious causality" which is a cognitive dead end.