Agrin in Alzheimer’s disease: Altered solubility and abnormal distribution within microvasculature and brain parenchyma

Agrin is a heparan sulfate proteoglycan that is widely expressed in neurons and microvascular basal lamina in the rodent and avian central nervous system. Agrin induces the differentiation of nerve-muscle synapses, but its function in either normal or diseased brains is not known. Alzheimer’s disease (AD) is characterized by loss of synapses, changes in microvascular architecture, and formation of neurofibrillary tangles and senile plaques. Here we have asked whether AD causes changes in the distribution and biochemical properties of agrin. Immunostaining of normal, aged human central nervous system revealed that agrin is expressed in neurons in multiple brain areas. Robust agrin immunoreactivity was observed uniformly in the microvascular basal lamina. In AD brains, agrin is highly concentrated in both diffuse and neuritic plaques as well as neurofibrillary tangles; neuronal expression of agrin also was observed. Furthermore, patients with AD had microvascular alterations characterized by thinning and fragmentation of the basal lamina. Detergent extraction and Western blotting showed that virtually all the agrin in normal brain is soluble in 1% SDS. In contrast, a large fraction of the agrin in AD brains is insoluble under these conditions, suggesting that it is tightly associated with β-amyloid. Together, these data indicate that the agrin abnormalities observed in AD are closely linked to β-amyloid deposition. These observations suggest that altered agrin expression in the microvasculature and the brain parenchyma contribute to the pathogenesis of AD.

Opposite roles of apolipoprotein E in normal brains and in Alzheimer’s disease

We have characterized the interaction between apolipoprotein E (apoE) and amyloid β peptide (Aβ) in the soluble fraction of the cerebral cortex of Alzheimer’s disease (AD) and control subjects. Western blot analysis with specific antibodies identified in both groups a complex composed of the full-length apoE and Aβ peptides ending at residues 40 and 42. The apoE–Aβ soluble aggregate is less stable in AD brains than in controls, when treated with the anionic detergent SDS. The complex is present in significantly higher quantity in control than in AD brains, whereas in the insoluble fraction an inverse correlation has previously been reported. Moreover, in the AD subjects the Aβ bound to apoE is more sensitive to protease digestion than is the unbound Aβ. Taken together, our results indicate that in normal brains apoE efficiently binds and sequesters Aβ, preventing its aggregation. In AD, the impaired apoE–Aβ binding leads to the critical accumulation of Aβ, facilitating plaque formation.

Fluorescent light-induced chromatid breaks distinguish Alzheimer disease cells from normal cells in tissue culture.

The neurodegeneration and amyloid deposition of sporadic Alzheimer disease (AD) also occur in familial AD and in all trisomy-21 Down syndrome (DS) patients, suggesting a common pathogenetic mechanism. We investigated whether defective processing of damaged DNA might be that mechanism, as postulated for the neurodegeneration in xeroderma pigmentosum, a disease with defective repair not only of UV radiation-induced, but also of some oxygen free radical-induced, DNA lesions. We irradiated AD and DS skin fibroblasts or blood lymphocytes with fluorescent light, which is known to cause free radical-induced DNA damage. The cells were then treated with either beta-cytosine arabinoside (araC) or caffeine, and chromatid breaks were quantified. At least 28 of 31 normal donors and 10 of 11 donors with nonamyloid neurodegenerations gave normal test results. All 12 DS, 11 sporadic AD, and 16 familial AD patients tested had abnormal araC and caffeine tests, as did XP-A cells. In one of our four AD families, an abnormal caffeine test was found in all 10 afflicted individuals (including 3 asymptomatic when their skin biopsies were obtained) and in 8 of 11 offspring at a 50% risk for AD. Our tests could prove useful in predicting inheritance of familial AD and in supporting, or rendering unlikely, the diagnosis of sporadic AD in patients suspected of having the disease.

Index generalis rerum notabilium, quae continentur in Theatro veritatis, [et] justitiae, ejusque supplemento ... D. Joh. Baptistae cardinalis de Luca ... /

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De laudibus sancti Stanislai Kostkae e Societate Jesu oratio latino sermone conscripta ab Alderano Allegrini ac deinde ab eodem in vernaculam linguam conversa ...

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Imago optimi Episcopi siue De vita, et virtutibus V. Raymundi Marimonii vicensis in ausetanis Episcopi : liber singularis /

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Herculis Marescotti ... Variarum resolutionum liber primus [et] secundus : in quibus selectiores vtriusque iuris materiae tam beneficiales quam prophanae quae apud omnia tribunalia frequentius in disputationem veniunt, nec non dubia [et] quaestiones, quae in vtraq[ue] ; signatura S.D.N. Papae ac in Sacro Rotae Romanae Auditorio [et] et in Regio Consilio Neapolis ...

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Academica expositio ad titulum de regulis iuris, ex libro sexto Decretalium domini Bonifacii VIII P.M. /

Contiene: Extemporanea repetitio ad Gregorium IX in cap. cum in causa. ultimo de Iuramento Calumniae... / ... Doctor D. Ferdinandus de Meneses et Pedrosa .... 63 p.

Synopsis florae germanicae et helveticae, exhibens stirpes phanerogamas rite cognitas, quae in Germania, Helvetia, Borussia et Istria sponte crescunt atque in hominum usum copiosius coluntur.

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Glossarium ad statuta bremensia antiqua,

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Disputatio literaria, qua examinatur quam vim sophistae habuerint Athenis ad aetatis suae disciplinam, mores ac studia immutanda. [Inaugural dissertation.]

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Analecta ad historiam rei metallicae veterum.

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Hermippus redivivus; sive, Exercitatio physico-medica curiosa de methodo rara ad CXV annos prorogandae senectutis.

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Micae historico-chronologicae evangelico-pannonicae skiagraphikōs /

Cover title: Johannis Burii Micae historiae evangelicorum in Hungaria ab anno 1673 ad 1688 annum.

Notitia dignitatum et administrationum omnium tam civilium quam militarium in partibus Orientis et Occidentis.

Each vol. has general t.p. dated 1839-53 and undated special t.p.