β-amyloid oligomers and cellular prion protein in Alzheimer’s disease

Prefibrillar oligomers of the β-amyloid peptide (Aβ) are recognized as potential mediators of Alzheimer’s disease (AD) pathophysiology. Deficits in synaptic function, neurotoxicity, and the progression of AD have all been linked to the oligomeric Aβ assemblies rather than to Aβ monomers or to amyloid plaques. However, the molecular sites of Aβ oligomer action have remained largely unknown. Recently, the cellular prion protein (PrP^C) has been shown to act as a functional receptor for Aβ oligomers in brain slices. Because PrP^C serves as the substrate for Creutzfeldt–Jakob Disease (CJD), these data suggest mechanistic similarities between the two neurodegenerative diseases. Here, we review the importance of Aβ oligomers in AD, commonalities between AD and CJD, and the newly emergent role of PrP^C as a receptor for Aβ oligomers.     

Amyloid protein of vessels in leptomeninges, cortices, choroid plexuses, and pituitary glands from patients with systemic amyloidosis

The cerebrum, cerebellum, and choroid plexuses from 16 patients with systemic amyloidosis, and the pituitary glands from 14 of these patients, were investigated histologically and immunohistochemically. Cerebrovascular amyloid (CVA) was found in the leptomeninges and cortices of six patients with systemic amyloidosis, including two patients with amyloid A protein (AA) amyloidosis related to serum amyloid A protein, one with AL amyloidosis related to immunoglobulin light chain (AL), two with familial type I amyloidotic polyneuropathy (FAP), and one with senile systemic amyloidosis (SSA). CVA protein from two patients with FAP reacted with anti-human prealbumin antibody similar to that of the visceral organs of these two patients. CVA in SSA reacted with anti-human prealbumin antibody and anti-beta protein antibody. Vascular amyloid was frequently noted in the pituitary glands and choroid plexuses of patients with systemic amyloidosis, and was found to be identical to that in the visceral organs (heart, kidney, and intestine) of these patients. CVA in the leptomeninges and cortices from two patients with AA amyloidosis and one with AL amyloidosis reacted with anti-beta protein monoclonal antibody but not with anti-human AA monoclonal antibody, anti-human A lambda antisera, and anti-human A kappa antisera. We suggest that amyloid proteins of AA and AL amyloidosis do not readily accumulate in the vessels in the leptomeninges and cortices even though the proteins circulate, and that beta protein is not derived from a serum precursor.     

Cerebral Amyloid Angiopathy : Amyloid β Accumulates in Putative Interstitial Fluid Drainage Pathways in Alzheimer’s Disease

Cerebral amyloid angiopathy in Alzheimer’s disease is characterized by deposition of amyloid β (Aβ) in cortical and leptomeningeal vessel walls. Although it has been suggested that Aβ is derived from vascular smooth muscle, deposition of Aβ is not seen in larger cerebral vessel walls nor in extracranial vessels. In the present study, we examine evidence for the hypothesis that Aβ is deposited in periarterial interstitial fluid drainage pathways of the brain in Alzheimer’s disease and that this contributes significantly to cerebral amyloid angiopathy. There is firm evidence in animals for drainage of interstitial fluid from the brain to cervical lymph nodes along periarterial spaces; similar periarterial channels exist in humans. Biochemical study of 6 brains without Alzheimer’s disease revealed a pool of soluble Aβ in the cortex. Histology and immunocytochemistry of 17 brains with Alzheimer’s disease showed that Aβ accumulates five times more frequently around arteries than around veins, with selective involvement of smaller arteries. Initial deposits of Aβ occur at the periphery of arteries at the site of the putative interstitial fluid drainage pathways. These observations support the hypothesis that Aβ is deposited in periarterial interstitial fluid drainage pathways of the brain and contributes significantly to cerebral amyloid angiopathy in Alzheimer’s disease.     

Mitochondrial respiratory inhibition and oxidative stress elevate β-secretase (BACE1) proteins and activity in vivo in the rat retina

Cerebral hypometabolism, oxidative stress and β-amyloid peptide (Aβ) accumulation are key pathological events in Alzheimer’s disease (AD). Beta-secretase (BACE, i.e., BACE1), a prerequisite for Aβ genesis, is elevated in sporadic AD. Recent studies show BACE upregulation in experimental conditions likely associated with energy insufficiency and/or oxidative stress. We investigated the effect of sublethal doses of mitochondrial respiratory inhibitors and potential endogenous oxidative substances on BACE expression in vivo using the retina as a model. Retinas were analyzed biochemically and anatomically 48 h following intraocular applications of mitochondrial complex I, II and IV inhibitors including rotenone, 3-nitropropionic acid and sodium azide, and plaque-containing oxidants including Fe³⁺ and Aβ42 fibrils (Aβ42f). All agents caused elevations of BACE proteins and β-site amyloid precursor protein (APP) cleavage product, β-CTF, in retinal lysates in a dose-dependant manner. BACE activity and Aβ40 levels were also increased in agent-treated retinas relative to vehicle controls. BACE immunoreactivity in normal adult rat retina was present mostly in the plexiform layers, indicating a localization of the enzyme to synaptic terminals. No apparent change in laminar or cellular distribution of BACE labeling was detected in the experimental retinas. However, signs of neuronal stress including glial activation were observed in agent-treated retinas especially in high dosage groups. Our data suggest that mitochondrial respiratory inhibition and oxidative stress facilitate BACE expression in vivo. In addition, plaque constituents such as Fe³⁺ and Aβ42f may participate in a self-enforcing cycle of amyloidogenesis via BACE upregulation.     

Novel therapeutic approach for Alzheimer’s disease by removing amyloid β protein from the brain with an extracorporeal removal system

The accumulation of amyloid beta (Aβ) protein in the brain reflects the cognitive impairment noted in Alzheimer’s disease. Recent studies have shown that brain Aβ disappeared and cognitive improvement occurred as a result of passive or active Aβ immunization. Peripheral administration of nonimmunization substances, such as GM1 ganglioside, also reduced brain Aβ. Therefore, we hypothesized that the rapid removal of Aβ from the blood by an extracorporeal system may act as a peripheral Aβ sink from the brain. In the present study, we investigated the Aβ removal activity of medical materials as a first step toward the design of an Aβ removal system. First, the removal activities of six materials were studied for Aβ_1–40 and Aβ_1–42 by batch analysis in albumin solution or in human plasma for 1–16 h. Two of the six materials reduced the Aβ concentrations by 90–99% within 1 h. Next, the two effective materials, hexadecyl-alkylated cellulose particles (HDC) and charcoal, were analyzed in a continuous single-pass system with minicolumns. Both materials showed around 81–90% removal activity for more than 2 h, which corresponded to over 4 l of plasma treatment in humans. In a human extracorporeal system, HDC also removed both Aβ_1–40 and Aβ_1–42 from whole blood circulation. In conclusion, biomedical materials were found that could remove Aβ_1–40 and Aβ_1–42 effectively in an extracorporeal system. It is now conceivable that further studies can be undertaken to reduce Aβ concentrations in the brain to improve cognitive function.     

Visceral organ involvement and extracellular matrix changes in β2-microglobulin amyloidosis – a comparative study with systemic AA and AL amyloidosis

 Patterns of amyloid distribution and extracellular matrix changes in the heart and gastrointestinal tract were compared among β₂-microglobulin (B2M), AA (secondary), and AL (primary and multiple myeloma-associated) amyloidosis cases. B2M amyloid was found to be mainly distributed in the small arterioles, venules, endocardium and muscularis propria of these organs, the deposits characteristically forming subendothelial nodular lesions in the vessels. A marked increase of chondroitin sulfate (CS) was consistently detected in B2M amyloid. Heparan sulfate (HS) also showed an increase in amyloid deposits, but with less reactivity than CS in the small arterioles or venules. Basement membrane structures stained positively for laminin and collagen type IV were replaced by negative amyloid deposits. In the AL cases, the muscularis propria of the gastrointestinal tract was involved in amyloid deposits, as seen for the B2M type, but the vascular amyloid deposits were localized in the media and adventitia of larger vessels. Immunoreactivity for HS was more intense than that for CS, and no increase in laminin or collagen type IV was observed. In the AA cases, amyloid deposits were distributed in the capillaries, small arterioles, interstitium of the myocardium and mucosa. Immunoreactivity for laminin and collagen type IV was marked, and more intense than that for HS and CS. Although the existence of a direct relationship between increase in extracellular matrix material and amyloidogenesis remains to be proven, the observed variation in extracellular matrix changes in the background of each type of amyloidosis may indicate different binding sites of the amyloid precursor proteins, resulting in the specific histological features and distribution. Received: 23 August 1996 / Accepted: 9 January 1997     

Hexapeptides HLDF-6 and PEDF-6 restore memory in rats after chronic intracerebroventricular treatment with β-amyloid peptide Aβ(25–35)

Effects of homologous peptides HLDF-6 and PEDF-6 on behavior of animals with experimental Alzheimer’s disease induced by chronic intracerebroventricular administration of β-amyloid peptide Aβ(25–35) were studied in the zoosocial recognition test and Morris water maze. Peptides HLDF-6 and PEDF-6 possessed neuroprotective activity and counteracted the toxic effect of Aβ(25–35). Peptides HLDF-6 and PEDF-6 mainly improved long-term memory and working memory, respectively. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 3, pp. 292–296, March, 2006     

Alterations in presenilin 1 processing by amyloid-β peptide in the rat retina

Accumulating evidence indicates that mutations in the presenilin 1 (PS1) gene are responsible for most cases of familial Alzheimer’s disease (AD). Although its biological functions are not yet fully understood, it appears that PS1 plays a role in the processing and trafficking of the amyloid precursor protein (APP). However, little is known about factors that are involved in regulating the metabolism of PS1 especially in relation to AD pathology. In this study, we have examined the effect of optic nerve crush, intravitreal injection of the inflammatory agent lipopolysaccharide (LPS) or injection of amyloid β_1-42 (Aβ_1-42) on the expression and processing of PS1 in the rat retina. We found that 48 h after injection of Aβ_1-42 there was a dramatic alteration in the banding pattern of PS1 on Western blots, as indicated by marked changes in the levels of expression of some of its C- and N-terminal fragments in retinal homogenates. These results suggest an Aβ_1-42-induced potentiation of a non-specific stress-related but inflammation-independent alteration of processing of PS1 in this in vivo model.     

Oligomeric and fibrillar species of β-amyloid (Aβ42) both impair mitochondrial function in P301L tau transgenic mice

We recently provided evidence for a mitochondrial dysfunction in P301L tau transgenic mice, a strain modeling the tau pathology of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). In addition to tau aggregates, the AD brain is further characterized by Aβ peptide-containing plaques. When we addressed the role of Aβ, this indicated a synergistic action of tau and Aβ pathology on the mitochondria. In the present study, we compared the toxicity of different Aβ42 conformations in light of recent studies suggesting that oligomeric rather than fibrillar Aβ might be the actual toxic species. Interestingly, both oligomeric and fibrillar, but not disaggregated (mainly monomeric) Aβ42 caused a decreased mitochondrial membrane potential in cortical brain cells obtained from FTD P301L tau transgenic mice. This was not observed with cerebellar preparations indicating selective vulnerability of cortical neurons. Furthermore, we found reductions in state 3 respiration, the respiratory control ratio, and uncoupled respiration when incubating P301L tau mitochondria either with oligomeric or fibrillar preparations of Aβ42. Finally, we found that aging specifically increased the sensitivity of mitochondria to oligomeric Aβ42 damage indicating that oligomeric and fibrillar Aβ42 are both toxic, but exert different degrees of toxicity. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Dexamethasone diminishes the pro-inflammatory and cytotoxic effects of amyloid β-protein in cerebrovascular smooth muscle cells

Background  

Cerebrovascular deposition of fibrillar amyloid β-protein (Aβ), a condition known as cerebral amyloid angiopathy (CAA), is a prominent pathological feature of Alzheimer's disease (AD) and related disorders. Accumulation of cerebral vascular fibrillar Aβ is implicated in promoting local neuroinflammation, causes marked degeneration of smooth muscle cells, and can lead to loss of vessel wall integrity with hemorrhage. However, the relationship between cerebral vascular fibrillar Aβ-induced inflammatory responses and localized cytotoxicity in the vessel wall remains unclear.     

Diagnosis and immunohistochemical classification of systemic amyloidoses

 Fourty-three cases of systemic amyloidosis were identified in an unselected autopsy series from our institute (6305 autopsies between 1979 and 1993) and classified immunohistochemically by means of a panel of antisera directed against five major amyloid fibril proteins. Amyloid A (AA) amyloidosis was the most common type, being found in 21 cases (48.8%). Transthyretin-derived (ATTR) amyloidosis was present in 11 cases (25.6%), and immunoglobulin light chain-derived (AL) amyloidosis in 10 cases (23.3%). A single case (2.3%) contained deposits of more than one type of systemic amyloid. AA amyoloidosis was associated with chronic inflammatory or infectious diseases (81%), malignant tumours (19%) or both (9.5%). Immunoglobulin light chain-derived amyloidoses were associated with myeloma (50%) or primary (idiopathic; 50%). In AA and AL amyloidosis the kidney was the organ most frequently involved. ATTR amyloid affecting mostly the heart and lungs presented as senile systemic amyloidosis. Systemic amyloidosis was the cause of death in 5 cases (12%) and caused symptoms in 17 cases (39%). Our results suggest that most cases can be classified by using a panel of sensitive and specific antibodies against five major amyloid fibril proteins. This technique may make amyloid type-specific therapy possible for AL amyloid patients who do not have evidence of an underlying plasma cell dyscrasia. Received: 9 December 1997 / Accepted: 2 February 1998     

The marijuana component cannabidiol inhibits β-amyloid-induced tau protein hyperphosphorylation through Wnt/β-catenin pathway rescue in PC12 cells

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. A massive accumulation of β-amyloid (Aβ) peptide aggregates has been proposed as pivotal event in AD. Aβ-induced toxicity is accompanied by a variegated combination of events including oxidative stress. The Wnt pathway has multiple actions in the cascade of events triggered by Aβ, and drugs that rescue Wnt activity may be considered as novel therapeutics for AD treatment. Cannabidiol, a non-psychoactive marijuana component, has been recently proposed as an antioxidant neuroprotective agent in neurodegenerative diseases. Moreover, it has been shown to rescue PC12 cells from toxicity induced by Aβ peptide. However, the molecular mechanism of cannabidiol-induced neuroprotective effect is still unknown. Here, we report that cannabidiol inhibits hyperphosphorylation of tau protein in Aβ-stimulated PC12 neuronal cells, which is one of the most representative hallmarks in AD. The effect of cannabidiol is mediated through the Wnt/β-catenin pathway rescue in Aβ-stimulated PC12 cells. These results provide new molecular insight regarding the neuroprotective effect of cannabidiol and suggest its possible role in the pharmacological management of AD, especially in view of its low toxicity in humans.     

Lmmunohistochemical classification of 140 autopsy cases with systemic amyloidosis

One hundred and forty autopsy cases of systemic amyloid-osis were examined using the potassium permanganate method for distinction of amyloid A protein from other amyloid proteins and an immunohistochemical technique. Of those cases, amyloid proteins were identified in 121 cases. There were 68 cases of amyloid A-related (AA) amyloidosis and these were the most common type among the cases (56.2%). There were 39 cases of immunoglobulin light chain-related (AL) amyloidosis (32.2%), six cases of β₂-microglobulin-related (Aβ2M) amyloidosis (5%), and five cases of transthyretin-related (ATTR) amyloidosis (4.1%). Minute areas of amyloid deposits in four cases with AA were resistant to potassium permanganate pretreatment. In Aβ2M amyloidosis amyloid deposits were either resistant or sensitive to potassium permanganate pretreatment, from case to case. The coexistence of two different amyloid proteins was seen in three cases: one case had ATTR and Ax types, and two cases had Aβ2M and AA types. Some discrepancies were seen between the immunohistochemical typing and clinical classification of amyloidosis referred to in the Annual of the Pathological Autopsy Cases in Japan, for example, one case of AA type in myeloma-associated amyloidosis and one case of AL type in secondary amyloidosis. From the present results, the importance of the immunohistochemical method in classifying amyloidosis is stressed.     

Modelling of amyloid β-peptide induced lesions using roller-drum incubation of hippocampal slice cultures from neonatal rats

Pronounced neurodegeneration of hippocampal pyramidal neurons has been shown in Alzheimer’s disease. The aim of this study was to establish an organotypic in vitro model for investigating effects of the amyloid β (Aβ)-peptide on pyramidal neuron degeneration, glial cell activation and tau phosphorylation. Tissue cultures in a quasi-monolayer were obtained using roller-drum incubation of hippocampal slices from neonatal Sprague Dawley rats. Neuronal populations identified included N-methyl-D-aspartate (NMDA-R1) receptor immunoreactive pyramidal neurons, and neurons immunopositive for glutamic acid decarboxylase-65 (GAD65) or gamma amino butyric acid (GABA). Many neurons expressed phosphorylated tau as shown by pS³⁹⁶, AD2 and PHF-tau immunostaining. Astrocytes, microglial cells and macrophages were also identified. The Aβ_25–35 peptide formed fibrillar networks within 2 days as demonstrated by electron microscopy. In the presence of the neurotoxic Aβ_25–35 peptide, but not Aβ_35–25, deposits developed in the tissue that were stainable with Thioflavine T and Congo red and showed the characteristic birefringence of Aβ plaques. Following Aβ_25–35 exposure, neurodegenerative cells were observed with Fluoro-Jade B staining. Further characterization of pyramidal neurons immunopositive for NMDA-R1 showed a decrease of cell number in the immediate surrounding of Aβ_25–35 deposits in a time- and concentration-dependent fashion. Similar effects on pyramidal neurons were obtained following exposure to the full-length, Aβ_1–40 peptide. Also, a loss of neuronal processes was seen with GAD65, but not GABA, immunohistochemistry after exposure to Aβ_25–35. Aβ_25–35-exposed neurons immunopositive for phospho-tau showed degenerating, bent and often fragmented processes. Astrocytes showed increased GFAP-positive reactivity after Aβ_25–35 exposure and formation of large networks of processes. No obvious effect on microglial cells and macrophages could be seen after the Aβ_25–35 exposure. The developed in vitro system may constitute a useful tool for screening novel drugs against Aβ-induced alterations of tau and degeneration of hippocampal neurons.     

Investigation of the Presence of Apotipoprotein E,G lycosaminoglycans,Basement Membrane Proteins,and Protease inhibitors in Senile interstitial Amyloid of the Pituitary

The aim of our study was to test whether local- or organ-limited interstitial amyloid of the pituitary is associated with the presence of glycosaminoglycans, basement membrane proteins, protease inhibitors, and apolipoprotein E (apo E), as previously observed in other amyloid syndromes. Serial sections from amyloidotic and nonamyloidotic autopsy pituitaries of patients age 85 yr and over were stained with Congo red, Alcian blue, and, applying immunohistochemistry, with antibodies directed against fibronectin, collagen IV, laminin, apo E, α₁-antitrypsin and α₁-antichymotrypsin. Interstitial amyloid was deposited in the immediate vicinity of capillaries and around the acini of the anterior lobe. Glycosaminoglycans were found in capillaries and around the acini of both nonamyloidotic and amyloidotic glands and they were also related spatially to amyloid deposits. Immunostatining of nonamyloidotic and amyloidotic glands demonstrated the presence of fibronectin, collagen IV, and laminin, which was related to basement membranes (fibronectin, collagen IV, and laminin), interstitium, and serum (fibronectin only). In amyloidotic glands, each basement membrane protein presented with an additional spatial relationship to amyloid deposits. Apo E was found in amyloidotic cases only within the amyloid deposits. The results are consistent with the presence of glycosaminoglycans, basement membrane proteins, and apo E in local interstitial amyloid deposits of the pituitary, as previously described in other amyloid syndromes, such as inflammatory related AA-amyloidosis or Aβ-amyloidosis related to Alzheimer’s disease.     

Inactivation of amyloid-enhancing factor (AEF): study on experimental murine AA amyloidosis

It is known that amyloid-enhancing factor (AEF) shortens the preamyloid phase in experimentally induced AA amyloidosis in mice. Because it is reported that AEF serves as both a nidus and a template for amyloid formation, AA amyloidosis may have transmissibility by a prion-like mechanism. It has been shown that amyloid fibrils also have AEF activity, and amyloid fibrils with AEF activity were named fibril-amyloid enhancing factor (F-AEF). In this study, we investigated methods to inactivate the AEF activity. AEF was extracted from the thyroid gland obtained at autopsy of a patient with AA amyloidosis. Before injection into mice, AEF was treated with several methods for inactivation. Of all the tested treatments, 1 N NaOH, 0.1 N NaOH, and autoclaving consistently demonstrated complete inactivation of AEF. Heat treatment led to incomplete inactivation, but 0.01 N NaOH, 0.001 N NaOH, pepsin, trypsin, pronase, and proteinase K treatment had no effect on AEF activity. By analysis with transmission electron microscopy, the AEF preparation contains amyloid fibrils, and a change of ultrastructure was shown after 1 N NaOH, 0.1 N NaOH, and autoclaving treatment. Furthermore, immunoblotting of AEF with antihuman AA antibody revealed that the protein band was scarcely found after autoclaving, 1 N NaOH, and 0.1 N NaOH treatment. Our results suggest that, similar to Creutzfeldt–Jakob disease (CJD), amyloidosis may require chemical or autoclaving decontamination.     

Induction of complement proteins in a mouse model for cerebral microvascular Aβ deposition

The deposition of amyloid β-protein (Aβ) in cerebral vasculature, known as cerebral amyloid angiopathy (CAA), is a common pathological feature of Alzheimer's disease and related disorders. In familial forms of CAA single mutations in the Aβ peptide have been linked to the increase of vascular Aβ deposits accompanied by a strong localized activation of glial cells and elevated expression of neuroinflammatory mediators including complement proteins. We have developed human amyloid-β precursor protein transgenic mice harboring two CAA Aβ mutations (Dutch E693Q and Iowa D694N) that mimic the prevalent cerebral microvascular Aβ deposition observed in those patients, and the Swedish mutations (K670N/M671L) to increase Aβ production. In these Tg-SwDI mice, we have reported predominant fibrillar Aβ along microvessels in the thalamic region and diffuse plaques in cortical region. Concurrently, activated microglia and reactive astrocytes have been detected primarily in association with fibrillar cerebral microvascular Aβ in this model. Here we show that three native complement components in classical and alternative complement pathways, C1q, C3, and C4, are elevated in Tg-SwDI mice in regions rich in fibrillar microvascular Aβ. Immunohistochemical staining of all three proteins was increased in thalamus, hippocampus, and subiculum, but not frontal cortex. Western blot analysis showed significant increases of all three proteins in the thalamic region (with hippocampus) as well as the cortical region, except C3 that was below detection level in cortex. Also, in the thalamic region (with hippocampus), C1q and C3 mRNAs were significantly up-regulated. These complement proteins appeared to be expressed largely by activated microglial cells associated with the fibrillar microvascular Aβ deposits. Our findings demonstrate that Tg-SwDI mice exhibit elevated complement protein expression in response to fibrillar vascular Aβ deposition that is observed in patients with familial CAA.     

Alpha 1-antichymotrypsin is associated solely with amyloid deposits containing the beta-protein. Amyloid and cell localization of alpha 1-antichymotrypsin

Our recent studies demonstrated that alpha 1-antichymotrypsin (ACT), a serine protease inhibitor, was associated with the beta-protein in the brain amyloid deposits of Alzheimer's disease, aged human controls and aged monkeys, suggesting a role for the inhibitor in the amyloid deposition. In the present study we used immunohistochemistry to test for the presence of ACT in the amyloid deposits which contain, as their major component, a protein different from the beta-protein. ACT was not found in the amyloid deposits in primary or secondary amyloidosis, familial and amyloidotic polyneuropathy or Creutzfeldt-Jakob disease (non-beta-protein amyloidoses), but was found (together with beta-protein) in Alzheimer's disease, Down's syndrome, normal aging, and hereditary cerebral hemorrhage with amyloidosis of Dutch origin. These results suggest a specific association of ACT with beta-protein amyloid. We next examined the distribution of the inhibitor in normal human brain and in various human neuropathological states in order to identify cells that express this protein during brain degeneration. In addition to its association with amyloid, ACT immunoreactivity was also located in astrocytes near areas of neuronal or tissue loss, in a few neurons and pericytes and in the epithelium of the choroid plexus.     

The effects of the total saponin of Dipsacus asperoides on the damage of cultured neurons induced by beta-amyloid protein 25-35

According to the pathogenesis of Alzheimer’s disease (AD), β-amyloid protein (Aβ) was directly toxic to neurons, leading to neurodegeneration. Total saponin of Dipsacus asperoides (tSDA) is one of the main ingredients of Dipsacus asperoide, a traditional Chinese medicine. To explore the effects of tSDA on neuronal damage induced by Aβ in vitro, biochemical analysis combining primary cultured neurons were adopted. Neurons were treated with 35 mmol/L Aβ for 24 h, and tSDA at concentrations of 1–300 mg/L were added to Aβ-treated cultures 24 h in advance, Aβ for 24 h, the survival rate of neurons decreased closely by 50%. Lactate dehydrogenase release and the Malondialdehyde (MDA) level increased substantially. However, if neurons were pretreated with tSDA, the survival rate of neurons was higher than Aβ-treated alone. Lactate dehydrogenase release and the MDA level decreased distinctly. Results demonstrated that tSDA possessed a neuroprotective action and that tSDA protected neurons against the toxicity of Aβ, most likely by relieving oxidative stress or inhibiting the process of Aβ, inducing free radical generation.     

Interleukin-1 receptor 1 knockout has no effect on amyloid deposition in Tg2576 mice and does not alter efficacy following Aβ immunotherapy

Background  

Microglial activation has been proposed to facilitate clearance of amyloid β protein (Aβ) from the brain following Aβ immunotherapy in amyloid precursor protein (APP) transgenic mice. Interleukin-1 receptor 1 knockout (IL-1 R1-/-) mice are reported to exhibit blunted inflammatory responses to injury. To further define the role of IL-1-mediated inflammatory responses and microglial activation in this paradigm, we examined the efficacy of passive Aβ immunotherapy in Tg2576 mice crossed into the IL-1 R1-/- background. In addition, we examined if loss of IL-1 R1-/- modifies Aβ deposition in the absence of additional manipulations.