Ultrastructural study of enriched fractions of “tangles” from human patients with senile dementia of the Alzheimer type

Summary Enriched fractions of tangles obtained from cases of Alzheimer's disease have been observed by negative staining and platinum: iridium shadowing, and also after treatment with sodium dodecyl sulfate and urea. Abnormal filaments with a 80-nm periodic constriction exhibited a substructure consisting of six protofilaments. They also showed a periodic right-handed twist. Some fibrils with a 160-nm periodic constriction were made up of four protofilaments. These features are discussed in view of known fibrous protein models, especially neurofilaments.Supported by grants from the Fonds de la Recherche Fondamentale Collective (No. 2.4517.82) and the Fonds National de la Recherche Médicale (No. 3.4512.82)     

Diffuse type of senile plaques in the cerebellum of Alzheimer-type dementia demonstrated byβ protein immunostain

Summary We studied senile plaques (SP) in the cerebella of six autopsied subjects with Alzheimer-type dementia (ATD) and ten non-ATD autopsied subjects between the ages of 78 and 90. Neither SP nor amyloid angiopathy (AA) was observed in any of the non-ATD subjects. In the four of the six ATD subjects, diffuse plaques in the molecular layer were seen as ill-defined areas of fine fibrillar materials by protein immunostaining with formic acid pretreatment, the modified Bielschowsky stain, and periodic acid-methenamine silver (PAM) stain. The plaques were not visible with Bodian, Congo red, or periodic acid-Schiff stains. Compact plaques in the Purkinje cell or in the granular cell layers were found in three of the six subjects. Their amyloid core was often surrounded by areolar amyloid deposits. AA was observed in three of the six subjects. The argyrophilia of the diffuse and compact plaques, demonstrated by the modified Bielschowsky and PAM stains, became undetectable when the sections were first treated with formic acid. Such treatment made the plaques immunoreactive with protein antiserum. The findings suggested that cerebellar diffuse plaques and compact plaques consist mainly of an amyloid component, and are characteristic of ATD.     

Spherulites in human brain tissue are composed of β sheets of amyloid and resemble senile plaques

Recent evidence showed that amyloid-β, Aβ(42), formed spherulites in vitro and, possibly, in vivo in Alzheimer's disease brain tissue. We now confirm the presence of spherulites in human brains and that they are composed of β sheets of amyloid. The spherulites were identical in appearance to spherulites of Aβ(42) formed in vitro which suggested that they may too be composed of Aβ. The physiological significance of this finding may be in its support of previous speculation that spherulites in human brain tissue are the 3-dimensional manifestations of what are otherwise identified as senile or neuritic plaques.     

Cdk5: one of the links between senile plaques and neurofibrillary tangles?

The relationship between amyloid plaques and neurofibrillary tangles, the two pathologic hallmarks of Alzheimer's disease (AD), is an unknown and controversial subject. However, emerging evidence from genetic and biochemical studies suggests that accumulation of amyloid beta peptides may play a causative role in AD pathogenesis. This led to the amyloid hypothesis, which proposes that amyloid beta peptides disrupt neuronal metabolic and ionic homeostasis and cause aberrant activation of kinases and/or inhibition of phosphatases. The resulting alteration in kinase and phosphatase activities ultimately leads to hyperphosphorylation of tau and formation of neurofibrillary tangles. Cyclin-dependent kinase 5 (Cdk5) is a tau kinase whose activity is induced by amyloid beta peptides. Its deregulation may represent one of the signal transduction pathways that connect amyloid beta toxicity to tau hyperphosphorylation. This article reviews the functions and regulation of Cdk5. Evidence that suggests deregulation of Cdk5 activity in AD by virtue of calpain cleavage of its activator p35 to p25 will be discussed.     

Deposition of β/A4 protein along neuronal plasma membranes in diffuse senile plaques

Summary The origin of the extracellular -amyloid protein (/A4) found in senile plaques and the cellular mechanisms responsible for its deposition in cerebral tissues are still an unresolved issue in Alzheimer's disease. In this study we analyzed in detail the distribution of various epitopes of /A4 in relation to local cellular elements in diffuse plaques of the hippocampal region. We also correlated our findings with the presence and distribution of non-/A4 epitopes of the amyloid precursor protein (APP) and with synaptophysin immunoreactivity in the cortical neuropil. Discontinuous /A4-immunoreactive deposits were found along dendrites, and around the soma of neurons included in the plaques. Furthermore, increased synaptophysin reactivity with slightly dilated synaptophysin-immunolabeled presynaptic terminals were found in diffuse plaques. APP epitopes could not be found in diffuse plaques. However, some of the APP antibodies, mainly those to the C-terminal portion of APP, and antibodies to /A4 recognized clusters of flat vesicular profiles (0.6–1.4 m in width and 2–3 m in length) in the neuropil of cortical areas where plaques had developed. Our findings are compatible with a neuronal origin of /A4 in diffuse plaques and with a primary release of /A4 at synaptic sites along the immunostained neurites. They also suggest that diffuse plaques might be preceded by minute lesions of the neuropil where /A4 is not yet released from the precursor molecule.     

Dystrophic neurites of senile plaques in Alzheimer’s disease are deficient in cytochrome c oxidase

Double-labeling immunofluorescence and confocal microscopy have been used to learn about the local relationship between amyloid, mitochondria, and cytochrome c oxidase (COX) in dystrophic neurites of senile plaques in the frontal cortex in Alzheimer's disease (AD). Dystrophic neurites surrounding amyloid plaques are filled with mitochondrial porin-immunoreactive structures. In contrast with tangle-bearing and non-tangle-bearing neurons, which express mitochondrial porin and COX subunit 4, porin-immunoreactive neurites of senile plaques lack COX subunit 4. Parallel western blot studies in mitochondria-enriched fractions of the frontal cortex in the same cases disclosed reduced expression levels of COX, but not of prohibitin, in AD stages VB/C of Braak. Co-localization of porin and lysosomal associated protein 1, as revealed by double-labeling immunofluorescence and confocal microscopy, suggests that mitochondria may be engulfed by lysosomes in dystrophic neurites. These findings support a local link between amyloid deposition, abnormal mitochondria and impaired respiratory chain function (resulting from decrease of COX expression) in dystrophic neurites of senile plaques in AD.     

A reproducible assay of polymerase chain reaction to detect trinucleotide repeat expansion of Huntington’s disease and senile chorea

Abstract

A simple and reproducible method of polymerase chain reaction (PCR) assay was established to detect trinucleotide repeat expansion for Huntington’s disease (HD) using a new DNA polymerase and buffer system. The system consists of an extremely heat stable DNA polymerase (Pfu), and a buffer supplemented with ammonium sulfate and dimethyl sulfoxide. Previous methods to amplify expanded alleles for HD have been very complex in PCR conditions; but the reproducibility was sometimes very low because of repetitive sequences around the primer sequences. With the present method’ strong bands for the disease alleles were reproducibly visible in a conventional agarose gel stained with ethidium bromide without using isotopes. Three cases with sporadic HD and a case with senile chorea showed expanded alleles for HD with smaller sizes of the expansion than cases with typical HD. These results showed that the present method provides a simple and reproducible way to detect HD allele, and some cases with sporadic HD and senile chorea had expanded HD alleles. [Neurol Res 1996; 18: 16–18]     

Ultrastructural localization of Alzheimer amyloid β/A4 protein precursor in the cytoplasm of neurons and senile plaque-associated astrocytes

Summary The ultrastructural localization of amyloid /A4 protein precursor (APP) in the brains of control and Alzheimer's disease patients was examined immunohistochemically using antisera against the N and C termini of APP. In both control and Alzheimer brains, immunoreaction for APP was seen in the cytoplasm of most neurons, on plasma membranes, outer membrane of mitochondria, granular substance and neurofilaments. Cell bodies and foot processes of astrocytes, containing glial filaments, were also labeled. In primitive and classic type senile plaques, APP immunoreaction products were localized in the astroglial processes that surrounded the amyloid mass of the senile plaques. Swollen degenerating neurites in the senile plaques were also labeled. Amyloid fibrils were negative with APP antisera.Supported by Grant-in-Aid for Scientific Research on Priority Area 02240105 from the Ministry of Education, Science, and Culture, Japan     

Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree--a new disease?

The term Lewy body disease (LBD) was proposed earlier to describe a disease classified into three types (A, B, and C) according to the distributional pattern of Lewy bodies in the CNS. Group A (diffuse type of LBD) shows clinical symptoms of "dementia-parkinsonism syndrome". The most remarkable pathologic feature is the widespread appearance of numerous Lewy bodies not only in the brain stem and diencephalon (as in group C), but also in the cerebral cortex and basal ganglia, which is complicated by senile changes of various degrees. Group B is the transitional type between groups A and C. Group C (brain stem type of LBD) is identical with idiopathic Parkinson's disease. In this paper, 12 of our cases with diffuse type LBD were studied clinicopathologically and compared with eight similar cases in the literature. The neuropathologic substrate of progressive dementia in this disease is also discussed. LBD is a clinicopathologic entity; the diffuse type of LBD, a special form of this disease, presents mainly a presenile dementia.     

Is silica involved in neuritic (senile) plaque formation?

Summary The agent responsible for inducing neuritic (senile) plaque formation in senile dementia of the Alzheimer's type and in the ageing non-demented brain is unknown. Other workers have detected a high concentration of silicon in the rims and cores of senile neuritic plaques. We have therefore looked at whether the reaction of brain tissue to silica particles resembles a neuritic plaque. In this study both fine (10 nm) and coarse (<5 m) particles of silica have been introduced into the brains of rats and mice using a wide range of doses and several methods of administration. The reaction of the brain to the presence of the silica was examined by light and electronmicroscopy up to one year after the injection.The presence of silica particles in the brain resulted in the proliferation of fibrous astrocytes and macrophages and strongly stimulated the production of collagen fibres. Degeneration of some adjacent axons and axon terminals occurred, but there was no detectable deposition of amyloid which is characteristic of senile plaques. Coarse particles of silica invariably produced a more intense reaction than fine particles. The reaction of the brain did not diminish with time within one year of injection.The possible significance of the presence of silica in the plaque as a secondary phenomenon is discussed.Supported by a National Health and Medical Research Council Grant     

What to look for beyond "pathogenic" factors in senile dementia? A functional deficiency of Ca²⁺ signaling

We have contended that senile conditions--illnesses after age 60 and fully age-penetrating, such as tooth, hearing or memory loss--are not distinct "diseases" in medical nature, because they are caused by aging. Since the pace of aging varies among individuals and is much influenced by risk factors, senile conditions will only affect some but not all elderly. However, perhaps due to its unusually heavy burdens and tremendous social pressures, senile dementia (SD) has been singled out from other senile conditions and redefined as a curable "disease" (Alzheimer's). This highly popular definition has thus opened a Pandora's box that has been confusing us up until now and warrants further scrutiny. In this article we discuss: a) what should we logically look for in SD beyond "pathogenic" factors?; b) why Ca2+, a central regulator in neurotransmission, should be the primary player in SD; c) why the functionality of Ca2+ signaling, or its vibrant wave frequency and amplitude, must undergo down-regulation during aging, though this is intriguingly accompanied by an increase of Ca2+ "levels"; d) why intervention for SD should target Ca2+ function by promoting energy metabolisms and by Ca2+ agonists such as caffeine and nicotine, but not by "antagonists" as widely believed; and e) why our study should focus on aging, not "cell death", a seemingly attractive paradigm but perhaps too late for intervention. We also seek answers for why unproven hypotheses can become dogmas and inhibit self-correcting mechanisms of science.     

Präsenile Demenz vom Alzheimer-Typ mit sekundärem Parkinson-Syndrom

This case report describes long-term occupational exposure to agricultural insecticides, herbicides, and pesticides as possible environmental risk factors of Alzheimer's disease (AD) and Parkinson's syndrome in a 59-year-old man. Initially the patient complained about disturbances in concentration, mnestic deficits, and problems finding words. In the further course of the disease, he developed Parkinson's syndrome with predominant hypokinesia and rigor in addition to mild-to-moderate dementia. Low levels of beta-amyloid 1-42 were found in the CSF. Electroencephalography showed left frontotemporal theta waves. Cranial MRI revealed general brain atrophy with a maximum biparietally. In cerebral positron emission tomography, general hypometabolism was found with maxima biparietally and left frontally. The possible differential diagnosis of AD and Parkinson's syndrome is discussed.     

„Kongophile Angiopathie“ und „senile Plaques“ bei greisen Hunden

Zusammenfassung Bei einer Serie von 20 senilen Hunden konnte bei 6 Tieren eine kongophile Angiopathie der Meningealund Gehirngefäße aufgezeigt werden, die der beim alternden und altersentarteten Menschen beobachteten vollkommen gleicht.Erstmals gelang bei sehr alten Hunden — und somit in der Tierreihe überhaupt — der eindeutige Nachweis seniler Plaques in ihrer amorphen Form.Die biologischen Prinzipien des alternden Menschenund Tiergehirns liegen, wie das Beispiel der senilen Hunde klar zeigt, grundsätzlich auf einer Ebene: Es handelt sich physikalisch um fortschreitende Synäresis mit ihren primären und sekundären Auswirkungen am Gewebe, wobei über den Chemismus selbst nichts ausgesagt werden kann.Herrn Professor Dr. K. Neubuerger, Denver (Col.) zugeeignet. — Gerade 30 Jahre sind vergangen, seitdem mich K. Neubuerger als jungen Hilfsarzt von Eglfing in die Histopathologie des Zentralnervensystems einführte. In den trüben Jahren, die über die Anstaltspsychiatrie hingingen, brachte die wissenschaftliche Arbeit Trost und Hilfe. Möge das Ergebnis der vorliegenden Arbeit, die ein vor 30 Jahren angegangenes Problem wieder aufgreift, schönster Dank für Professor Neubuergers Mühe von einst sein.     

On the behaviour of senile dementia patients vis-à-vis the mirror: Ajuriaguerra, Strejilevitch and Tissot (1963)

Mirror agnosia is the inability to use mirror knowledge when interacting with mirrors, while mirrored-self misidentification is the delusional belief that one's reflection in the mirror is a stranger. Ajuriaguerra, Strejilevitch, and Tissot (1963) conducted a detailed study of these two conditions before they became widely known in the English literature. We present a translation of this important paper. In their study, Ajuriaguerra et al. (1963) examined the behaviour of 30 dementia patients with respect to the mirror. Their examination focussed on three criteria: (1) recognition of own reflection; (2) use of reflected space; and (3) designation of parts of the body. The study found three distinct levels of impairment when interacting with mirrors. Patients with the most severe dementia were unable to recognise their own reflection and displayed the mirrored-self misidentification delusion. Patients with moderate dementia showed mirror agnosia. Finally, patients with mild dementia were unable to designate parts of their body in the mirror. These findings have important implications for understanding mirror agnosia and the mirrored-self misidentification delusion. In a commentary, we discuss the importance of the findings and place them within the context of subsequent research.     

Präsenile Demenzen in Gedächtnisambulanzen — Konsultationsinzidenz und Krankheitscharakteristika

This study describes the clinical features of presenile dementia diagnosed in memory clinics. It further gives an estimate of the declared incidence for the German city of Munich and surrounding counties. Twelve memory clinics in Switzerland and Germany were considered, among them all of the four in Munich. A total of 267 patients with onset of illness under the age of 65 were included. Only 16 patients (6%) were younger than 50. Men and women were affected about equally often. The most common cause of dementia was Alzheimer's disease (67%), followed by frontotemporal degeneration (13.5%) and vascular (5.6%) dementia. The declared incidence was estimated at 8.3 new cases of dementia per year among 100,000 persons in the 50-64 age range, with an incidence rate of Alzheimer's disease at 6.3/100,000. It can be concluded that memory clinics fulfill an important function in the care of patients with presenile dementia, since they are highly utilized by younger patients in early stages of the illness.