Deposition of Alzheimer’s vascular amyloid-β is associated with decreased expression of brain -3-hydroxyacyl-coenzyme A dehydrogenase (ERAB)

-3-hydroxyacyl-coenzyme A dehydrogenase type II (HADH) was described as an endoplasmic reticulum amyloid β-peptide-binding protein (ERAB), which enhances Aβ toxicity, and accumulates in neurons in Alzheimer’s disease (AD). Hence, HADH/ERAB was suggested to mediate the amyloid-induced neurodegeneration. We estimated the in vivo interactions of HADH and Aβ in an immunocytochemical study of ten Alzheimer’s disease and seven normal brains using five monoclonal HADH-specific antibodies. We found no HADH in amyloid plaques or vascular amyloid. The neuronal expression of HADH was not correlated with the severity of amyloid load in neuropil. HADH was expressed in vascular smooth muscle cells in young and old controls and in amyloid-free blood vessels in AD cases, but little or no HADH was in smooth muscle cells in arteries with amyloid deposits. The putative intracellular interaction between HADH and Aβ in amyloid-producing cells was further studied in vascular smooth muscle cells isolated from brain blood vessels with amyloid-β angiopathy — the cells that were shown previously to accumulate Aβ intracellularly [‘Research advances in Alzheimer’s disease and related disorders’ (1995) 747; Brain Res. 676 (1995) 225; Neurosci. Lett. 183 (1995) 120]. HADH had a mitochondrial localization and did not co-localize with an endoplasmic reticulum marker. Cells that accumulated Aβ were those with low expression of HADH and the proteins did not co-localize. Explanation of the association between low levels of HADH and deposition of Aβ by brain smooth muscle cells requires further studies.     

Amyloid-β: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-β

Although much maligned, the amyloid-β (Aβ) protein has been shown to possess a number of trophic properties that emanate from the protein’s ability to bind Cu, Fe and Zn. Aβ belongs to a group of proteins that capture redox metal ions (even under mildly acidotic conditions), thereby preventing them from participating in redox cycling with other ligands. The coordination of Cu appears to be crucial for Aβ’s own antioxidant activity that has been demonstrated both in vitro as well as in the brain, cerebrospinal fluid and plasma. The chelation of Cu by Aβ would therefore be predicted to dampen oxidative stress in the mildly acidotic and oxidative environment that accompanies acute brain trauma and Alzheimer’s disease (AD). Given that oxidative stress promotes Aβ generation, the formation of diffuse amyloid plaques is likely to be a compensatory response to remove reactive oxygen species. This review weighs up the evidence supporting both the trophic and toxic properties of Aβ, and while evidence for direct Aβ neurotoxicity in vivo is scarce, we postulate that the product of Aβ’s antioxidant activity, hydrogen peroxide (H₂O₂), is likely to mediate toxicity as the levels of this oxidant rise with the accumulation of Aβ in the AD brain. We propose that metal ion chelators, antioxidants, antiinflammatories and amyloid-lowering drugs that target the reduction of H₂O₂ and/or Aβ generation may be efficacious in decreasing neurotoxicity. However, given the antioxidant activity of Aβ, we suggest that the excessive removal of Aβ may prevent adequate chelation of metal ions and removal of O₂⁻, leading to enhanced, rather than reduced, neuronal oxidative stress.     

Methionine residue 35 is important in amyloid β-peptide-associated free radical oxidative stress

Amyloid β-peptide (Aβ), the central constituent of senile plaques in Alzheimer’s disease (AD) brain, has been shown to be a source of free radical oxidative stress that may lead to neurodegeneration. In the current study Aβ(1-40), found in AD brain, and the amyloid fragment Aβ(25-35) were used in conjunction with electron paramagnetic resonance spin trapping techniques to demonstrate that these peptides mediate free radical production. The methionine residue in these peptides is believed to play an important role in their neurotoxicity. Substitution of methionine by structurally similar norleucine in both Aβ(1-40) and Aβ(25-35), and the substitution of methionine by valine, or the removal of the methionine in Aβ(25-35), abrogates free radical production and protein oxidation of and toxicity to hippocampal neurons. These results are discussed with relevance to the hypothesis that neurodegeneration in Alzheimer’s disease may be due in part to Aβ-associated free radical oxidative stress that involves methionine, and to the use of spin trapping methods to infer mechanistic information about Aβ.     

Apolipoprotein E deposition and astrogliosis are associated with maturation of β-amyloid plaques in βAPPswe transgenic mouse: Implications for the pathogenesis of Alzheimer’s disease

A transgenic mouse expressing the human β-amyloid precursor protein with the ‘Swedish’ mutation, Tg2576, was used to investigate the mechanism of β-amyloid (Aβ) deposition. Previously, we have reported that the major species of Aβ in the amyloid plaques of Tg2576 mice are Aβ_1-40 and Aβ_1-42. Moreover, Aβ_1-42 deposition precedes Aβ_1-40 deposition, while Aβ_1-40 accumulates in the central part of the plaques later in the pathogenic process. Those data indicate that Aβ deposits in Tg2576 mice have similar characteristics to those in Alzheimer’s disease. In the present study, to understand more fully the amyloid deposition mechanism implicating Alzheimer’s disease pathogenesis, we examined immunohistochemically the distributions of apolipoprotein E (apoE) and Aβ in amyloid plaques of aged Tg2576 mouse brains. Our findings suggest that Aβ_1-42 deposition precedes apoE deposition, and that Aβ_1-40 deposition follows apoE deposition during plaque maturation. We next examined the relationship between apoE and astrogliosis associated with amyloid plaques using a double-immunofluorescence method. Extracellular apoE deposits were always associated with reactive astrocytes whose processes showed enhancement of apoE-immunoreactivity. Taken together, the characteristics of amyloid plaques in Tg2576 mice are similar to those in Alzheimer’s disease with respect to apoE and astrogliosis. Furthermore, apoE deposition and astrogliosis may be necessary for amyloid plaque maturation.     

β-amyloid Peptides and Amyloid Plaques in Alzheimer’s Disease

Many lines of evidence support that β-amyloid (Aβ) peptides play an important role in Alzheimer’s disease (AD), the most common cause of dementia. But despite much effort the molecular mechanisms of how Aβ contributes to AD remain unclear. While Aβ is generated from its precursor protein throughout life, the peptide is best known as the main component of amyloid plaques, the neuropathological hallmark of AD. Reduction in Aβ has been the major target of recent experimental therapies against AD. Unfortunately, human clinical trials targeting Aβ have not shown the hoped-for benefits. Thus, doubts have been growing about the role of Aβ as a therapeutic target. Here we review evidence supporting the involvement of Aβ in AD, highlight the importance of differentiating between various forms of Aβ, and suggest that a better understanding of Aβ’s precise pathophysiological role in the disease is important for correctly targeting it for potential future therapy.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-014-0313-y) contains supplementary material, which is available to authorized users.Key Words: Dementia, Alzheimer’s disease, amyloid precursor protein, amyloid, therapy     

Statins: drugs for Alzheimer’s disease?

Summary. Evidences from cell culture experiments and animal studies suggest a strong link between cholesterol and Alzheimer’s disease (AD). This relationship is supported by retrospective epidemiological studies demonstrating that statin treatment reduced the prevalence of AD in patients suffering from hypercholesterolaemia. The alternative processing of the amyloid-precursor protein (APP) in the brain of AD patients leads to the production of the neurotoxic amyloid-beta protein (Aβ), a causative factor for AD pathology. In vitro, this mechanism is modulated by alterations in cellular cholesterol levels. Moreover, lowering cholesterol in animal experiments reduced the production of Aβ in most but not all studies. These findings led to prospective clinical trials of cholesterol-lowering statins in AD patients, even if many studies do not support elevated cholesterol levels in serum and brain as a risk factor for Alzheimer’s disease. Most of these studies were negative. Thus, up to date there is insufficient evidence to suggest the use of statins for treatment in patients with AD.     

Platelet secretion of β-amyloid is increased in hypercholesterolaemia

Tissue accumulation of the cytotoxic β-amyloid peptide (Aβ) occurs in Alzheimer’s disease (AD), one possible source being the platelet. AD and cardiovascular disease may share some risk factors, including hypercholesterolaemia which is associated with increased platelet activity. We examined platelet Aβ release under resting and collagen-stimulated conditions in normocholesterolaemic and hypercholesterolaemic individuals. Resting platelet Aβ efflux was greater in hypercholesterolaemics than in normocholesterolaemics. Collagen-stimulated Aβ release was concentration-dependent and increased in hypercholesterolaemics. Resting Aβ release correlated positively with plasma total cholesterol and low-density lipoprotein (LDL) cholesterol, and inversely with platelet count. These data indicate that abnormal platelet Aβ release occurs in hypercholesterolaemia.     

Ferulic Acid Ameliorates Alzheimer’s Disease-like Pathology and Repairs Cognitive Decline by Preventing Capillary Hypofunction in APP/PS1 Mice

Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of brain capillaries is triggered by beta-amyloid (Aβ) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aβ plaque deposition, the primary pathophysiology of Alzheimer’s disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aβ plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aβ plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aβ plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aβ plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01024-7.Key Words: Alzheimer’s disease, APP/PS1 mouse, Aβ plaque, Hippocampus, Endothelin-1, Ferulic acid (FA)     

PEN–2 gene mutation in a familial Alzheimer’s disease case

Genetic evidence indicates a central role of cerebral accumulation of β–amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD). Beside presenilin 1 and 2, three other recently discovered proteins (Aph 1, PEN 2 and nicastrin) are associated with γ–secretase activity, the enzymatic complex generating Aβ. Alterations in genes encoding these proteins were candidates for a role in AD. The PEN 2 gene was examined for unknown mutations and polymorphisms in sporadic and familial Alzheimer patients. Samples from age–matched controls (n = 253), sporadic AD (SAD, n = 256) and familial AD (FAD, n = 140) were screened with DHPLC methodology followed by sequencing. Scanning the gene identified for the first time a missense mutation (D90N) in a patient with FAD. Three intronic polymorphisms were also identified, one of which had a higher presence of the mutated allele in AD subjects carrying the allele ε4 of apolipoprotein E than controls. The pathogenic role of the PEN–2 D90N mutation in AD is not clear, but the findings might lead to new studies on its functional and genetic role.*These two authors contributed equally to the paper.     

Alzheimer's disease genetic mutation evokes ultrastructural alterations: Correlation to an intracellular Aβ deposition and the level of GSK-3β-P(Y216) phosphorylated form

Herein we demonstrate that PC12 cells, which overexpress human wild-type amyloid-β precursor protein (AβPPwt) or AβPP bearing double Swedish mutation (AβPPsw), reveal phenotype characteristic for Alzheimer's disease (AD). The examination of cell ultrastructure showed the presence of peptide aggregates within the cells, activation of endosomal–lysosomal system and extensive exocytosis. Furthermore, the autophagy induction was also characteristic hallmark of amyloid-β-induced cytotoxicity. Morphological changes were positively correlated with the extent of phosphorylated glycogen synthase kinase-3β (phospho-Tyr²¹⁶-GSK-3β, GSK-3β-P(Y216)). The activity of GSK-3β is believed to cause tau protein hyper-phosphorylation, increased amyloid-β production and local plaque-associated microglial-mediated inflammatory responses. All of them are symptomatic for AD. In our studies, the highly significant Y216 phosphorylation and over-expression of total GSK-3β were observed in AβPPsw-transfected PC12 cells. In addition, the immuocytochemical analysis showed co-localization of GSK-3β-P(Y216) and amyloid-β deposits. Thus, our data support a functional role of GSK-3β in AβPP processing, further implicating this kinase in the amyloid-β-dependent pathogenesis.     

Molecular mechanism of neurodegeneration induced by Alzheimer’s β-amyloid protein: channel formation and disruption of calcium homeostasis

The etiology of Alzheimer’s disease has been suggested to be linked to the neurodegeneration induced by β-amyloid protein (AβP), however, the mechanism underlying the latter remains unknown. We have previously shown the direct incorporation of AβP into neuronal membranes of immortalized hypothalamic neurons (GT1-7 cells) associated with the formation of calcium-permeable pores, and the elevation of the intracellular calcium concentrations in the GT1-7 cells. Taking together our results and those of numerous other studies, we hypothesize that the disruption of calcium homeostasis by AβP-channels may be the molecular basis of the neurotoxicity of AβP, and the development of Alzheimer’s disease. It is also proposed that the constituents of membrane lipids may play important roles in the process of this channel formation. Our hypothesis may also explain the mechanism of development of other ‘conformational diseases’, such as prion disease or type 2 diabetes mellitus, which share some common features with Alzheimer’s disease.     

Reduction of cerebrospinal fluid amyloid β after systemic administration of M1 muscarinic agonists

Overproduction of the peptide amyloid β (Aβ) is a critical event in Alzheimer’s disease (AD). Systemic administration of 3 M1-selective muscarinic agonists, AF102B, AF150S and AF267B, decreased cerebrospinal fluid (CSF) Aβ concentrations; levels of CSF secreted β-APP were not significantly altered. Rabbits treated for 5 days with s.c. injections of each drug (2 mg/kg/day) had levels of CSF Aβ which were between 55 and 71% of control for Aβ 1–40 and between 59 and 84% of control for Aβ 1–42.     

An update on the toxicity of Aβ in Alzheimer’s disease

Alzheimer’s disease is characterized histopathologically by deposition of insoluble forms of the peptide Aβ and the protein tau in brain. Aβ is the principal component of amyloid plaques and tau of neurofibrillary tangles. Familial cases of AD are associated with causal mutations in the gene encoding the amyloid precursor protein, APP, from which the amyloidogenic Aβ peptide is derived, and this supports a role for Aβ in disease. Aβ can promote tau pathology and at the same time its toxicity is also tau-dependent. Aβ can adopt different conformations including soluble oligomers and insoluble fibrillar species present in plaques. We discuss which of these conformations exert toxicity, highlight molecular pathways involved and discuss what has been learned by applying functional genomics.     

Genes and susceptible loci of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common and devastating neurodegenerative disease of the elderly. Many research findings on familial AD suggest that the mechanisms of the pathogenesis of the disorder is more complex although the overall neuropathology of all cases of AD is surprisingly very similar. Genetic studies on some families have shown that mutations in the genes encoding β-amyloid precursor protein and presenilins 1 and 2 are responsible for early-onset AD. In addition, apolipoprotein E gene allele E4 and the bleomycin hydrolase locus are shown to be genetic risk factors for late-onset AD in certain sporadic cases. Mitochondrial dysfunctions and age-related oxidative stress may also contribute to degenerative processes in AD. Although several studies support the amyloid cascade hypothesis as the mechanism of the disease, transgenic experiments and recent findings on a variant form of an AD family suggest that Aβ deposition may not be sufficient to cause AD. Identification in the future of other genetic, environmental, and age-related factors, may provide additional targets for therapies.     

Tau and transgenic animal models

Advances in genetics and transgenic approaches have a continuous impact on our understanding of Alzheimer’s disease (AD) and related disorders, especially as aspects of the histopathology and neurodegeneration can be reproduced in animal models. AD is characterized by extracellular Aβ peptide-containing plaques and neurofibrillary aggregates of hyperphosphorylated isoforms of microtubule-associated protein tau. A causal link between Aβ production, neurodegeneration and dementia has been established with the identification of familial forms of AD which are linked to mutations in the amyloid precursor protein APP, from which the Aβ peptide is derived by proteolysis. No mutations have been identified in the tau gene in AD until today. Tau filament formation, in the absence of Aβ production, is also a feature of several additional neurodegenerative diseases including progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The identification of mutations in the tau gene which are linked to FTDP-17 established that dysfunction of tau can, as well as Aβ formation, lead to neurodegeneration and dementia. In this review, newly recognized cellular functions of tau, and the neuropathology and clinical syndrome of FTDP-17 will be presented, as well as recent advances that have been achieved in studies of transgenic mice expressing tau and AD-related kinases and phosphatases. These models link neurofibrillary lesion formation to neuronal loss, provide an in vivo model in which therapies can be assessed, and may contribute to determine the relationship between Aβ production and tau pathology.     

Ruthenium Red Colorimetric and Birefringent Staining of Amyloid-β Aggregates in Vitro and in Tg2576 Mice

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Presenilin Is Essential for ApoE Secretion,a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis

Alzheimer''s disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β (Aβ) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENT Familial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-β 42 (Aβ42)/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aβ clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.     

Abundant expression of zinc transporters in the amyloid plaques of Alzheimer's disease brain

The pathological key features of Alzheimer's disease (AD) are β-amyloid peptide (Aβ)-containing senile plaques (SP) and neurofibrillary tangles. Previous studies have suggested that an extracellular elevation of the zinc concentration can initiate the deposition of Aβ and lead to the formation of SP. In the present study, we present data showing a correlation between zinc ions, zinc transporters (ZNTs) and AD, using immersion autometallography (AMG) and double immunofluorescence for the ZNTs and Aβ. We found that all the ZNTs tested (ZNT1, 3, 4, 5, 6, 7) were extensively present in the Aβ-positive plaques in the cortex of human AD brains, and the density of autometallographic silver enhanced zinc–sulphur nanoparticles were much higher in the plaques than in the surrounding zinc enriched (ZEN) terminals. Moreover, we found an abundant expression of ZNT3 and autometallographic grains in the amyloid angiopathic vessels. The subcellular localization of ZNTs and zinc ions were not detected, due to the limited tissue preservation in the present study. In conclusion, our data provided significant morphological evidence of zinc ions and ZNTs being actively involved in the pathological processes that lead to plaque formation.     

The Natural Product Betulinic Acid Rapidly Promotes Amyloid-β Fibril Formation at the Expense of Soluble Oligomers

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Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer’s disease

Advanced glycation end products (AGE) and the receptor for AGE (RAGE) have been implicated in the chronic complications of diabetes mellitus (DM), and have been reported to play an important role in the pathogenesis of Alzheimer’s disease (AD). In this study, we established a polyclonal anti-RAGE antibody, and examined the immunohistochemical localization of amyloid β protein (Aβ), AGE, and RAGE in neurons and astrocytes from patients with AD and DM. Our anti-RAGE antibody recognized full-length RAGE (50 kd) and N-terminal RAGE (35 kd) in human brain tissue. Aβ-, AGE-, and RAGE-positive granules were identified in the perikaryon of hippocampal neurons (especially from CA3 and CA4) in all subjects. The distribution and staining pattern of these immunopositive granules showed good concordance with each antibody. In AD, most astrocytes contained both AGE-and RAGE-positive granules and their distribution was almost the same. Aβ-positive granules were less common, but Aβ-, AGE-, and RAGE-positive granules were colocalized in one part of a single astrocyte. In DM patients and control cases, AGE-and RAGE-positive astrocytes were very rare. These finding support the hypothesis that glycated Aβ is taken up via RAGE and is degraded through the lysosomal pathway in astrocytes. In addition to the presence of AGE, the process of AGE degradation and receptor-mediated reactions may contribute to neuronal dysfunction and promote the progression of AD.