Transgenic mouse models for Alzheimer's disease: the role of GSK-3B in combined amyloid and tau-pathology

Describing and understanding the pathological processes which devastate the brain of Alzheimer's disease (AD) patients remains a major target for experimental biology. We approached this problem by generating different types of single and double transgenic mice that develop pathological hallmarks of AD. In APP-V717 mice, the progression from intracellular amyloid to diffuse and senile plaques with vascular deposits, is preceded by early defects in cognition and LTP. In Tau-P301L mice, the morbid tauopathy with intracellular filaments, cause mortality before age 1 year. Ageing APP-V717IxTau-P301L double tg mice (14-17 months) have combined AD-like pathology in hippocampus and cortex consisting of amyloid plaques and neurofibrillary tangles. Remarkably, while Tau-P301L mice die before age 1 year, the APP-V717IxTau-P301L double tg mice survive much longer, which correlates with alleviation of tauopathy in hindbrain, despite aggravation in forebrain. This hypothesis is corroborated in Tau-P301LxGSK-3B double transgenic mice, which have also an extended lifespan relative to Tau-P301L mice, that correlates with reduction of brainstem tauopathy. At the same time, Tau-P301LxGSK-3B mice have dramatic forebrain tauopathy, with "tangles in almost all neurons", although without hyper-phosphorylation of Tau. The data corroborate the hypothesis that GSK-3B is the missing link between the amyloid and tau-pathology, and position GSK-3B as prominent player in the pathogenesis in AD.     

Truncated tau at D421 is associated with neurodegeneration and tangle formation in the brain of Alzheimer transgenic models

In addition to tau hyperphosphorylation, tau truncation is also detected in Alzheimer’s disease (AD) patients. In the brain of AD transgenic mouse models, the pathological details of truncated tau are not well characterized. In this study, we analyzed spatial relationships among tau truncation, tau phosphorylation and neurodegeneration or tangle formation in a tau^P301L single transgenic mouse model and a triple transgenic mouse model that produces both amyloid plaques, and neurofibrillary tangles. During development of tau pathology, the spatial relationship between hyperphosphorylation and truncation of tau exhibited a shift from colocalization at low densities of hyperphosphorylated tau to partial dissociation at high densities. Importantly, we detected a few neurons that contained abundant truncated tau but were lacking hyperphosphorylation, and these neurons exhibited remarkable nuclear condensation. In the case of colocalization, truncated tau was commonly associated with high immunoreactivity of hyperphosphorylated tau and dense Gallyas silver staining. Taken together, our study shows that tau truncation appears after tau hyperphosphorylation in the brain of two transgenic mouse models, and that accumulation of truncated tau, in the absence or the presence of phosphorylated tau, is closely associated with a subset of neurons undergoing degeneration or containing neurofibrillary tangles.     

Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer''s disease neurofibrillary degeneration

Cyclin-dependent kinase 5 (cdk5) is one of the candidate kinases involved in the abnormal hyperphosphorylation of tau. To have a direct effect on tau hyperphosphorylation, cdk5 protein levels and enzyme activity should be upregulated in especially those neurons that develop neurofibrillary tangles (NFTs). We studied the distribution of cdk5 immunoreactivity in neurons with or without early- and late-stage NFTs in hippocampal, entorhinal, transentorhinal, temporal and frontal cortices, and cerebellum of Alzheimer's disease (AD) and control brain. The immunocytochemical localisation of cdk5 was compared with that obtained using antibodies to PHF-tau (tau in paired helical filaments of NFTs, mAb AT8) and ubiquitin as markers of early and late stage NFTs, respectively. Immunoreactivities of cdk5 and PHF-tau were found in neuronal perikarya and processes of hippocampal, entorhinal, transentorhinal, temporal and frontal, and cerebellar cortices. An apparent increase of cdk5 immunoreactivity was seen in pretangle neurons and in neurons bearing early stage NFTs. These findings suggest that this kinase might be involved in the formation of NFTs at a relatively early stage in the neocortex.     

Brainstem Alzheimer's-like pathology in the triple transgenic mouse model of Alzheimer's disease

The triple transgenic mouse (3xTgAD), harboring human APP_Swe, PS1_M146V and Tau_P301L genes, develops age-dependent forebrain intraneuronal Aβ and tau as well as extraneuronal plaques. We evaluated brainstem AD-like pathology using 6E10, AT8, and Alz50 antibodies and unbiased stereology in young and old 3xTgAD mice. Intraneuronal Aβ occurred in the tectum, periaqueductal gray, substantia nigra, red nucleus, tegmentum and mesencephalic V nucleus at all ages. Aβ-positive neuron numbers significantly decreased in the superior colliculus and substantia nigra while AT8-positive superior colliculus, red nucleus, principal sensory V, vestibular nuclei, and tegmental neurons significantly increased between 2 and 12 months. Alz50-positive neuron numbers increased only in the inferior colliculus between these ages. Dual labeling revealed a few Aβ- and tau-positive neurons. Plaques occurred only in the pons of female 3xTgAD mice starting at 9 months. 3xTgAD mice provide a platform to define in vivo mechanisms of Aβ and tau brainstem pathology.     

Relationship between microtubule-binding repeats and morphology of neurofibrillary tangle in Alzheimer's disease

OBJECTIVE: The present study was performed to compare the distributions of three-repeat (3R) and four-repeat (4R) neurofibrillary tangles (NFT) with those of pretangles (p-NFT), intracellular NFT (i-NFT), and extracellular NFT (e-NFT) in the hippocampus of Alzheimer's disease brains. METHODS: NFT labeling was performed using anti-tau antibodies: pSer262 for p-NFT, pSer422 for i-NFT, AT8 for e-NFT, RD3 for 3R, and RD4 for 4R tau, and Gallyas impregnation for the NFT population. RD4- and pSer422-positive NFT were detected predominantly in sectors from CA2 to CA4, while RD3- and pSer262-positive NFT were predominantly present in CA1, the entorhinal cortex, and the subiculum. The tau epitope recognized by pSer262 belongs to 4R tau but it showed a strong correlation with RD3- and AT8-positive NFT. CONCLUSIONS: Sectors CA2-CA4 showed predominantly 4R-NFT containing the pSer422 epitope. pSer262 may detect the process of transformation from p-NFT to i-NFT, and e-NFT consisted predominantly of 3R tau.     

Progressive supranuclear palsy: extensive neuropil threads in addition to neurofibrillary tangles

Summary Light microscopic immunohistochemical investigations were performed on neurofibrillary tangles (NFT) in four histologically confirmed cases of Alzheimer's disease (AD) and in five patients with a progressive supranuclear palsy (PSP). The antibody panel included antisera to the neuronal microtubule-associated protein, tau, and to isolated paired helical filaments (PHF), as well as mouse monoclonal antibodies (MAbs) to phosphorylated epitopes on high and medium molecular weight neurofilament subunits (RT97 and BF10, respectively). Paraffin sections were also impregnated with the Gallyas silver method, which specifically stains tangles and cortical neuropil threads in AD, but does not stain normal neurofilaments. All tangles in PSP and AD showed consistent immunostaining with antibodies to tau protein and isolated PHF, regardless of their localization. MAbs RT97 and BF10, however, did not stain or only weakly stained, subcortical tangles in PSP and AD, whereas most cortical NFT in AD were intensely immunostained. All tangles in PSP were as heavily impregnated with Gallyas as they were in AD. Furthermore there were extensive networks of Gallyaspositive, tau- and PHF-immunoreactive neurites in subcortical gray areas containing NFT, and bundles of positive axons in white matter tracts interconnecting subcortical nuclei of PSP. Our studies indicate a much more extensive disruption of fibrillar proteins in PSP subcortical neurons than previously reported. They furthermore indicate a very similar antigenic profile of NFT in PSP and AD, as far as subcortical neurons are concerned.     

Distribution of cortical neurofibrillary tangles in progressive supranuclear palsy: A quantitative analysis of six cases

Summary Progressive supranuclear palsy is characterized neuropathologically by the presence of high densities of neurofibrillary tangles in several subcortical structures. In some cases, neurofibrillary tangles have also been described in the cerebral cortex. We performed a quantitative regional and laminar analysis of the distribution of these lesions in six cases of progressive supranuclear palsy. We observed that the neurofibrillary tangle distribution in the cerebral cortex was largely confined to the hippocampal formation. In particular, in all the cases neurofibrillary tangles were observed in the granule cell layer of the dentate gyrus. In the prefrontal and inferior temporal cortex, neurofibrillary tangles were predominantly distributed in layers II and III. In addition, there were moderate-to-high neurofibrillary tangle densities in the primary motor cortex. This localization pattern contrasts with the neurofibrillary tangle distribution observed in the cerebral cortex of Alzheimer's disease cases, where tangles are denser in layer V than in layer III, and where the primary motor cortex and the dentate gyrus are usually not involved. These results suggest that specific elements of the cortical circuitry might be differentially vulnerable in progressive supranuclear palsy as compared to Alzheimer's disease.Supported in part by the Brookdale Foundation and the American Health Assistance Foundation (to PRH), and ADERMA and INSERM clinical network CAR 489016 (to AD)     

Immunocytochemistry of neurofibrillary tangles with antibodies to subregions of tau protein: identification of hidden and cleaved tau epitopes and a new phosphorylation site

Summary Antibodies to multiple epitopes spanning the length of the tau molecule were used to study Alzheimer neurofibrillary tangles (NFT) using immunocytochemical methods and several differnt methods of fixation and tissue processing, including staining of vibratome sections, hydrated autoclaving of paraffin sections and immunofluorescence of NFT isolated from fresh brain tissue. Smears and sections were pretreated with trypsin and/or phosphatase to further characterize antibody binding. In tissue fixed briefly in periodate-lysine-paraformaldehyde, tau immunoreactivity was detected in astrocytes, but only a few tau epitopes were detected in NFT with this fixation method. In contrast, all tau epitopes were detected in NFT in tissue fixed in formaldehyde for prolonged periods of time. In the hippocampus, the number of NFT detected in the dentate fascia was in proportion to the duration of dementia, as we previously noted. Dentate fascia NFT were intracellular (i-NFT) and were reactive with antibodies recognizing epitopes in both the carboxy- and amino-terminal regions of tau, but not the microtubule-binding domain of tau, suggesting that microtubule-binding domain epitopes are hidden in i-NFT. In contrast, NFT in the subiculum and layer II of the parahippocampal cortex were mostly extracellular (e-NFT), especially in severe cases of long duration, e-NFT were immunoreactive with antibodies to the microtubule-binding domain, but only weakly reactive with antibodies to carboxy- or amino-terminal epitopes, suggesting that e-NFT may contain fragments of tau. In both isolated NFT and NFT in sections, amino-terminal epitopes, including the Alz-50 epitope, were sensitive to trypsin proteolysis, which suggests that the lack of staining of e-NFT by antibodies to the amino-terminal regions of tau is due to proteolysis. Antibodies reactive with amino-terminal epitopes also stained fewer NFT following hydrated autoclaving, while those reacting with the carboxy half of tau stained more NFT after hydrated autoclaving. Thus, although carboxy-terminal regions are not detected in e-NFT, they are probably masked, rather than proteolytically cleaved, since they can be revealed by hydrated autoclaving. Finally, phosphatase treatment of isolated NFT revealed enhanced immunostaining not only with Tau-1, as in previous studies demonstrating abnormal phosphorylation of tau proteins in NFT, but also with an antibody to exon 2, which reveals yet another phosphorylation site in tau of NFT.Supported by NIA AG06803, AG01136 and AG04145     

Alzheimer's disease: areal and laminar pathology in the occipital isocortex

Summary Sensitive and specific silver methods for demonstration of (1) amyloid and/or precursors of amyloid and (2) neurofibrillary changes were applied to examine the pathology revealed by the occipital isocortex in cases of Alzheimer's disease and age-matched controls. In general, amyloid and/or precursors of amyloid are encountered in plaque-like formations. Large numbers of amyloid plaques occur in layers that only occasionally harbor neuritic plaques. Amyloid deposits can be found in abundance in the occipital cortex of demented individuals exhibiting an only sparse number of neuritic plaques. In demented individuals the striate area contains almost as much amyloid as the parastriate area or the peristriate region. Neurofibrillary changes are encountered in neuritic plaques, neurofibrillary tangles, and neuropil threads. Neuritic plaques are predominantly found in layers II and III. Their density changes even within the boundaries of architectonic units. Large numbers of plaques are found in the cortex covering the depth of the sulci. The number of neurofibrillary tangles increases abruptly when passing the striate/parastriate and the parastriate/peristriate boundaries. The neuropil threads may densely fill a layer without the presence of neurofibrillary tangles (layer V of the striate area). Neuropil threads contribute a substantial part to the total amount of the intraneuronally deposited pathological material.Supported by the Deutsche Forschungsgemeinschaft     

Induction of epitopes associated with neurofibrillary tangles in clonal mouse neuroblastoma (S20Y) cells

Summary Accumulation of paired helical filaments (PHF) in neurofibrillary tangles is a key neuropathological hallmark in Alzheimer's disease (AD). To date, PHF have been found primarily in humans. Cultured murine cholinergic neuroblastoma (S20Y) cells, following exposure to a serum-free medium or a differentiation medium, developed immunoreactivity to anti-PHF antibodies, and to the Alz-50 by immunocytochemical and immunoblot analyses. Electron microscopic examination revealed abundant fascicles of 10-nm filaments coursing tortuously amongst organelles, such as mitochondria, endoplasmic reticulum and dense-core vesicles, in perikarya and in neuritic extensions. However, subcellular structures identical or similar to PHF could not be found in these non-human cells. This convenient cell culture model may prove to be useful for studying certain aspects of the mechanisms underlying the abnormal cytoskeletal alterations which are characteristic of AD and related neurodegenerative disorders.Supported by grants from the Overbrook Foundation, the Will Rogers Institute, the Dr. I. Fund Foundation, the Winifred Masterson Burke Relief Foundation, the Alzheimer's Disease Research Program of the American Health Assistance Foundation and the National Institute of Aging (AG03853)     

Lectin histochemistry of plaques and tangles in Alzheimer's disease

Summary Biotinyl derivatives of several lectins and avidin-horseradish peroxidase were used to study the localization of glycoconjugates in amyloid plaques and in neuritic tangles in brains of patients with Alzheimer's disease (AD), Downs syndrome (DS) and Gerstmann-Sträussler syndrome (GSS). The lectins tested recognize the following residues: -d-galactosyl [Ricinus communis agglutinin 120, (RCA-1) and peanut agglutinin, (PNA)]; -d-galactosyl [Griffonia simplicifolia agglutinin (GSA)]; -d-mannosyl>-d-glucosyl [concanavalin A (Con A) andLens culinaris agglutinin (LcH)];N-acetyl- andN-glycolylneuraminic acid [Limax flavus agglutinin (LFA) andLimulus polyphemus agglutinin (LPA)];N-acetyl-glucosaminyl and sialyl [wheat germ agglutinin (WGA)];N-acetyl-d-galactosaminyl [Helix pomatia agglutinin (HPA) andDolichos biflorus agglutinin (DBA)] and -l-fucosyl [Ulex europeus agglutinin (UEA-1)]. The majority of lectins listed above bind preferentially to the peripheral area of AD plaques, whereas in plaques of DS they are mainly bound to central amyloid core. In neurofibrillary tangles of AD brains only residues recognized by WGA and HPA or DBA were found, whereas in DS brains, in addition to above mentioned, -d-galactose (RCA-1) and sialic acid (LFA) were also present. In brain microblood vessels the strongest reaction in endothelia appeared with UEA-1 and RCA-1, indicating the abundance of -l-fucosyl and -d-galactosyl residues. In AD brains deposits of amyloid were noted in the wall of some blood vessels, where monosaccharide residues recognized by RCA-1, GSA, UEA and WGA but not by Con A and LFA were present. However, our studies of some organs (liver, kidney, heart and testes) of patients with generalized amyloidosis revealed a lack of these sugar residues. It indicates, that the composition of amyloid present in brains of AD is different to that in other organs in generalized amyloidosis.Supported in part by grant no. AG 04220-03 from the National Institute of Aging, NIH     

Accelerated extinction of conditioned taste aversion in P301L tau transgenic mice

Neurofibrillary tangles, insoluble protein deposits composed of filamentous tau aggregates, are neuropathological hallmarks of Alzheimer's disease and familial frontotemporal dementia (FTDP-17). Transgenic mice expressing the FTDP-17 mutation P301L of tau recapitulate key features of the human pathology, that is, tau proteins aggregate and neurofibrillary tangles begin to appear in the amygdala at 6 months of age. To detect early signs of tau aggregate-associated changes, we investigated behavioral alterations and cognitive deficits in such mice using an amygdala-specific test battery for anxiety-related and cognitive behavior. P301L mice had anxiety levels not different from wild-types, but their exploratory behavior was significantly increased. Acquisition of a fear response to tone and context as well as taste aversion was comparable to wild-types. However, extinction of a conditioned taste aversion was significantly accelerated. We conclude that already aggregation of tau proteins not yet accompanied by massive formation of neurofibrillary tangles causes selective behavioral deficits.     

Distribution of neurofibrillary tangle formation and [3H]-D-aspartate receptor binding in the thalamus in the normal elderly brain, in Alzheimer''s disease and in Parkinson''s disease

The overactivity of glutamatergic neurons may underlie some neurodegenerative disorders, including Alzheimer's disease (AD). We explored the relationship between glutamatergic transmission and neurofibrillary tangle formation by measuring [3H]-D-aspartate binding activity and the proportion of neurons containing tangles within individual thalamic nuclei in five AD cases. Five elderly normal and five Parkinson's disease (PD) cases were used as controls. A highly significant correlation between [3H]-D-aspartate binding and tangle counts in Alzheimer's disease suggests that those thalamic nuclei which normally receive a relatively dense glutamatergic afferent input are predisposed to tangle formation. There were no significant differences in individual thalamic nuclear [3H]-D-aspartate binding between controls and the AD and PD groups.     

Neurofibrillary tangle predominant form of senile dementia of Alzheimer type: a rare subtype in very old subjects

In a consecutive autopsy series of 580 demented elderly subject, 256 with the clinical diagnosis of probable/possible Alzheimer's disease (AD), there were 10 cases aged between 80 and 99 years with moderate to severe dementia or confusional state in which neuropathological studies revealed abundant neurofibrillary tangles with predominant involvement of the allocortex (entorhinal region, subiculum, CA 1 sector of hippocampus, amygdala) but no or only very few senile plaques. Small numbers of diffuse deposits of A4 amyloid protein were present in the entorhinal cortex of 3 and in the isocortex of 5 brains, while neuritic plaques were totally absent. Only a few cases of this senile dementia with tangles only or, more correctly, neurofibrillary predominant type of AD corresponding to the limbic stage of neuritic AD pathology have been described in the literature. This rare subtype occurring in very old (over 80 years of age) subjects that does not fall within the currently used neuropathological criteria for diagnosis of AD warrants further clinico-pathological documentation.     

Alzheimer neuropathology in mentally retarded adults: statistical independence of regional amyloid plaque and neurofibrillary tangle densities

Summary The densities of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed quantitatively in the brains of 303 mentally retarded adults 23 to 90 years of age at the time of their deaths (mean=59.5 years). Cases with Down's syndrome, hydrocephalus and metabolic disorders were excluded from the study. Examinations of frontal, temporal, parietal, and occipital cortex, as well as hippocampus and parahippocampal gyrus were made in every case. NPs and/or NFTs were observed within the brains of 163 cases (53.8%). Detailed analyses indicated that NP density within all brain regions examined was positively related to age, with the largest age associated increases in density seen in frontal and temporal regions. In contrast, NFT density increased with age only within hippocampus and parahippocampal gyrus, but not neocortex. In addition, NP lesions within neocortex were more diffusely distributed across regions for older compared to younger cases, while no similar age-associated change in the topography of NFTs was observed. Finally, factor analyses of the combined NP and NFT data indicated that, while strong correlations existed across the various brain regions for measures of NP and NFT densities, considered separately, there was virtually no indication of regional associations between these two types of lesions. While these data, from cases with mental retardation, cannot be generalized directly to the nonretarded population, they provide strong evidence that models of Alzheimer pathogenesis must take into account the fact that regional densities of NPs and NFTs, and, therefore, the underlying processes associated with formation of these lesions, can be largely independent.Supported by funds provided by New York State through its Office of Mental Retardation and Developmental Disabilities as well as by Grants PO1 HD22634, PO1 AGO4220, and R29 HD24170 from the National Institutes of Health     

Caspase-3-mediated cleavage of PHF-1 tau during apoptosis irrespective of excitotoxicity and oxidative stress: an implication to Alzheimer's disease

Excitotoxicity, oxidative stress, and apoptosis have been recognized as routes to neuronal death in various neurological diseases. We examined the possibility that PHF-1 tau, a substrate for various proteases, would be selectively cleaved depending upon routes of neuronal death. Cleavage form of PHF-1 tau was not observed in cortical cell cultures exposed to excitotoxins or oxidative stress that cause neuronal cell necrosis. PHF-1 tau was cleaved within 8 h following exposure of cortical cell cultures to apoptosis-inducing agents. This cleavage was blocked by inclusion of zDEVD-fmk, an inhibitor of caspase-3, and accompanied by activation of caspase-3. Levels and cleavage of PHF-1 tau were markedly increased in AD brain compared with control. Moreover, PHF-1 tau and active caspase-3 were colocalized mostly in tangle-bearing neurons. The current findings suggest that PHF-1 tau is cleaved by caspase-3 during apoptosis and neurodegenerative process in AD.     

Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer's disease cases

Summary Head trauma has been associated with the occurrence of Alzhiemer's disease and plays a clear role in the etiopathogenesis of the boxers encephalopathy referred to as dementia pugilistica. Neurofibrillary tangles (NFT), one of the pathological hallmarks of Alzheimer's disease are observed in very high densities in the brains of former professional boxers suffering from dementia pugilistica. In Alzheimer's disease, NFT display striking regional and laminar distribution patterns that have been correlated with the localization of neurons forming specific corticocortical connections. In dementia pugilistica cases, NFT were concentrated in the superficial layers in the neocortex, whereas in Alzheimer's disease they predominated in the deep layers. Thus, the association cortex of brains from dementia pugilistica patients demonstrated an inverse NFT distribution as compared to Alzheimer's disease. This finding suggests that a more circumscribed population of cortical pyramidal neurons might be affected in dementia pugilistica than in Alzheimer's disease.Supported by the Brookdale Foundation, the American Health Assistance Foundation, and NIH grants AG06647 and AG05138     

泛素在阿尔茨海默病神经原纤维缠结和老年斑中的表达

目的　观察泛素在阿尔茨海默病 (AD)患者和非痴呆 (ND)老年人脑海马神经原纤维缠结 (NFT)和老年斑 (SP)中的表达及分布特点 ,探讨泛素在AD发病机制中的意义。方法　采用免疫组织化学方法检测 7例AD、5例ND脑海马中泛素的表达及分布特点。结果　泛素在AD脑海马内的NFT和SP中特异性表达 ,而缠结前期神经元缺乏泛素免疫染色 ,同时海马CA1、CA2区泛素染色阳性的NFT神经元数目 (分别为 4 2 13± 0 6 5、30 5 7± 0 78)明显多于CA3、CA4区 (分别为 12 4 3±0 2 4、18 34± 0 81,P <0 0 1)。结论　泛素参与NFT形成的晚期发病机制 (晚期事件 ) ,失去正常功能的异常泛素可能是导致AD病理改变形成的重要因素之一 ;AD病理过程中海马CA1、CA2区病理改变较CA3、CA4区更为严重 ,提示CA1、CA2区神经元对AD的致病因素更为敏感     

Paired helical filaments are not the major binding sites for wheat germ and Dolichos biflorus agglutinins in the neurofibrillary tangles of Alzheimer's disease

Summary The isolated paired helical filaments (PHF) that occur in the neurofibrillary tangles of Alzheimer's disease were assayed to determine if they contained N-acetyl-glucosamine and N-acetyl-galactosamine residues. The enzyme-linked lectin assay was used to detect their total content in the PHF preparation. The assay employed biotinylated Dolichos biflorus and wheat germ agglutinins and was developed with avidin-horseradish peroxidase. The total PHF preparation was shown to contain very little of these glycosylated control proteins. Colloidal gold-labeled lectins were used to study the PHF by electron microscopy to assess whether the minor amount of lectin binding in the total preparation was directly associated with the PHF. These studies showed no significant association of the colloidal gold-labeled lectins with the isolated filaments. We conclude that the PHF themselves contain few or no N-acetyl-glucosamine or N-acetyl-galactosamine residues.Supported by an Advanced Technology Grant (J08166) from the Texas Higher Education Coordinating Board, a National Institutes of Health Alzheimer's Disease Research Center Grant (AG08013), and a grant from the French Foundation for Alzheimer Research     

Neurofibrillary changes confined to the entorhinal region and an abundance of cortical amyloid in cases of presenile and senile dementia

Summary Cases of old-aged demented individuals exhibited abundant cortical amyloid deposits but only small numbers of neurofibrillary changes. Neuritic plaques were rare or absent. Neither Ammon's horn nor isocortex revealed sufficiently large numbers of tangles to permit the diagnosis of fully developed Alzheimer's disease. Dense accumulations of neurofibrillary tangles and neuropil threads occurred only in layer Pre- (II) of the entorhinal region. This pattern of cortical destruction may represent a variant of Alzheimer's disease or an initial stage of this disorder.Supported by the Deutsche Forschungsgemeinschaft