Numerous Neurofibrillary Tangles Research Articles

Memantine/Aripiprazole Combination Alleviates Cognitive Dysfunction in Valproic Acid Rat Model of Autism: Hippocampal CREB/BDNF Signaling and Glutamate Homeostasis

SummarySignificant efforts are increasingly directed towards identifying novel therapeutic targets for autism spectrum disorder (ASD) with a rising role of aberrant glutamatergic transmission in the pathogenesis of ASD-associated cellular and behavioral deficits. This study aimed at investigating the role of chronic memantine (20 mg/kg/day) and aripiprazole (3 mg/kg/day) combination therapy in the management of prenatal sodium valproate (VPA)-induced autistic-like/cognitive deficits in male Wistar rats. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like behaviors in their offspring. Prenatal VPA induced autistic-like symptoms (decreased social interaction and the appearance of stereotyped behavior) with deficits in spatial learning (in Morris water maze) and cognitive flexibility (in the attentional set-shifting task) in addition to decreased hippocampal protein levels of phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and gene expression of glutamate transporter-1 (Glt-1) with a decline in GABA/glutamate ratio (both measured by HPLC). These were accompanied by the appearance of numerous neurofibrillary tangles (NFTs) with enhanced apoptosis in hippocampal sections. Memantine/aripiprazole combination increased the protein levels of p-CREB, BDNF, and Glt-1 gene expression with restoration of GABA/glutamate balance, attenuation of VPA-induced neurodegenerative changes and autistic-like symptoms, and improvement of cognitive performance. This study draws attention to the favorable cognitive effects of memantine/aripiprazole combination in autistic subjects which could be mediated via enhancing CREB/BDNF signaling with increased expression of astrocytic Glt-1 and restoration of GABA/glutamate balance, leading to inhibition of hippocampal NFTs formation and neuronal apoptosis.

Neuropathology of classic myotonic dystrophy type 1 is characterized by both early initiation of primary age-related tauopathy of the hippocampus and unique 3-repeat tauopathy of the brainstem.

Myotonic dystrophy type 1 (DM1) is an inherited autosomal-dominant condition that induces altered splicing of transcripts, including MAPT, leading to a distinctive abnormal deposition of tau protein in the CNS. We characterized the tau isoforms of abnormal depositions in the brains of 4 patients with classic DM1 by immunohistochemistry using isoform-specific antibodies. All patients, including those of presenile age, showed numerous neurofibrillary tangles (NFTs) of both 3-repeat and 4-repeat tau in the limbic area and mild involvement in the cerebral cortex. Amyloid-β deposition was only seen in 1 senile case while cortical tauopathy in all other cases was consistent with primary age-related tauopathy (PART). In the putamen and globus pallidus, only a few tau deposits were observed. Tau deposits in the brainstem frequently showed a DM1-specific pattern with 3-repeat tau dominant NFTs. Additionally, tau-positive astrocytes morphologically similar to tufted astrocytes and astrocytic plaques were occasionally observed in the brainstem; however, they were predominantly composed of 3-repeat tau. Thus, the classic DM1 showed both early onset of PART-like pathology in the limbic areas as a progeroid syndrome of DM1 and an abnormal splicing event in the brainstem leading to 3-repeat tau dominant accumulation with both neuronal and astrocytic involvement.

Structure of Tau filaments in Prion protein amyloidoses

In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

A review on the role of presenilin in alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia. It characterized by the presence of numerous senile plaques and neurofibrillary tangles in the cerebral cortex and hippocampus of affected individuals. Mutations in the genes encoding presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein have been identified as the main genetic causes of familial AD. To date, more than 200 mutations have been described worldwide in PSEN1, which is highly homologous with PSEN2, while mutations in PSEN2 have been rarely reported. We performed a review of studies describing the mutations identified in PSEN1 and PSEN2. This article brings about the information pertaining to the role of presenilin and its derivatives in Alzheimer's disease.

Inhibitory effects of Tabernaemontana divaricata root extract on oxidative stress and neuronal loss induced by amyloid β25–35 peptide in mice

In Alzheimer's disease, there are numerous amyloid plaques, neurofibrillary tangles, and neuronal loss in several brain areas. Oxidative stress is involved in the mechanisms of Aβ-peptide induced neurotoxicity by the generation of free radical oxidative stress that may lead to neurodegeneration. Tabernaemontana divaricata has various medical properties in Thai folklore medicine including prevent forgetfulness or improve memory. The present study aimed to investigate the effects of T. divaricata root extract (TDE) on Aβ25–35 peptides induced neuronal loss and oxidative stress in mice. Male ICR mice were administered with vehicle or TDE (250, 500, and 1000 mg/kg b.w., p.o.) for 28 consecutive days. Then, these mice were given a single intracerebroventricular (i.c.v.) injection of Aβ25–35 or phosphate buffer saline (PBS) (10 μg/mouse). The novel object recognition (NOR) test was used to determine memory disturbance. In addition, the neuronal cells in the cerebral cortex and hippocampus were measured by using crystal violet staining and lipid peroxidation was determined by measuring the formation of thiobarbituric acid reactive substances. An i.c.v. injection of Aβ25–35 peptides could significantly induce memory impairment, increase level of lipid peroxidation including the neuronal loss in CA3 of hippocampus. However, the mice pretreated with TDE could prevent the memory loss, neuronal loss and decrease lipid peroxidation. These results suggest the potential therapeutic value in dementia of TDE through its antioxidant property.

NEUROPATHOLOGY OF FAMILIAL ALZHEIMER'S DISEASE ASSOCIATED WITH A PRESENILIN 1 A396T MUTATION REVEALS THE COEXISTENCE OF Aβ, TAU, AND A-SYNUCLEIN PROTEINOPATHIES

In the course of a published, large molecular study of Alzheimer disease in Turkey, the Presenilin 1 (PSEN1) variant GCC to ACC was identified at c.1186 in the coding region of Exon 11. The same DNA change was found by analyzing archival brain tissue obtained by the National Cell Repository for Alzheimer’s Disease. A re-examination of the brain was carried out and available clinical records reviewed. DNA was isolated from frozen brain tissue and the APP and PSEN1 genes were sequenced. For histology, the following methods were used: Hematoxylin Eosin, Woelcke-Heidenhain, and Bielschowsky; for immunohistochemistry, antibodies against tau (ALZ-50), amyloid β (10D5), and α-synuclein were used. A 58 year old male complained of problems of concentration. At age 60, he noted word finding problems. An MRI, at age 61, showed atrophy and white matter changes more pronounced in the right occipital lobe; a SPECT scan at age 62 showed decreased perfusion in the right parietal lobe. The subject died at age 66. The subject’s father developed a dementing illness after age 65. The fresh brain weighed 1200 grams. The left hemibrain was examined neuropathologically, while the right hemibrain was frozen for molecular studies. Histologic and immuno-histochemical studies revealed numerous Lewy bodies and neurites in cingulate, frontal, insular, temporal, parietal and occipital cortices, in hippocampus, caudate nucleus, putamen, substantia innominata, amygdala, thalamus, substantia nigra, ocular motor nerve nucleus, locus coeruleus, and nucleus ambiguus. Numerous neurofibrillary tangles and neuritic plaques, tau immuno-positive neurons and neuropril threads, as well as Aβ immuno-positive plaques were also present in the above mentioned anatomical regions. Aβ angiopathy was noted. DNA analysis revealed a GCC>ACC point mutation predicting an amino acid substitution of Alanine (A) to Threonine (T) at residue 396 in Presenilin 1. This is the first study of the neuropathologic features associated with the PSEN1 A396T mutation. The neuropathologic diagnoses established prior to molecular analysis were: 1) Lewy body disease and 2) Alzheimer disease. The reexamination forces us to reconsider the neuropathologic diagnosis and potential pathogenetic mechanisms operating in the presence of PSEN1 mutations. Acknowledgements: P30 AG 010133; U24 AG 21886.

Tau accumulation in the nucleus accumbens in tangle-predominant dementia

BackgroundTangle-predominant dementia (TPD) is characterized neuropathologically by numerous neurofibrillary tangles in the limbic areas with no or occasional senile plaques throughout the brain. TPD is an under-recognized disease, while it is a common cause of dementia in those over 80 years of age. In the present study, we describe hyperphosphorylated tau (tau) accumulation in the nucleus accumbens (Acb) in patients with TPD.ResultsWe investigated immunohistochemically the brain tissues from 7 patients with TPD, 22 with Alzheimer disease (AD) and 11 non-demented aged subjects. In the Acb of all 7 TPD patients, a considerable number of tau positive neurons were found together with many neuropil threads. The tau deposits in the Acb were labeled with all the anti-tau antibodies used in the present study. They included conformational change-specific, phosphorylation-specific and phosphorylation-independent antibodies. The Acb consists of the predominant medium-sized neurons with a small number of large neurons. Both the cell types were affected by tau pathology in TPD. Tau accumulation in the majority of such neurons appeared to be pretangle-like, diffuse deposits with only occasional paired helical filament formation. Tau positive neurons were also found in the Acb in some AD and non-demented aged subjects but much fewer in the majority of cases. The immunoblot analyses of fresh frozen samples of the Acb and parahippocampal cortex from 3 TPD and 3 AD patients revealed that the insoluble tau in the Acb was a mixture of the 3- and 4-repeat isoforms.ConclusionsTo our knowledge, this is the first report on the occurrence of tau accumulation in the Acb in TPD. The Acb receives direct and massive projections from the hippocampal CA1 and subiculum where neurofibrillary tangles are known to occur more frequently in TPD than in AD. The prevalence of abnormal tau accumulation in the Acb in TPD may support the idea that abnormal tau aggregation propagates via neural circuits. In all but one TPD cases used in this study, delusion was a consistent clinical feature. Whether the Acb tau accumulation is related to the psychiatric symptoms in TPD may be an issue for further investigation.

Age-dependent effects of valproic acid in Alzheimer’s disease (AD) mice are associated with nerve growth factor (NGF) regulation

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes cognitive impairment. Major pathophysiological AD characteristics include numerous senile plaque, neurofibrillary tangles, and neuronal loss in the specific regions of patients’ brains. In this study, we aimed to understand disease stage-dependent regulation of histone modification for the expression of specific markers in plasma and the hippocampus of in vivo AD model. Since the control of histone acetylation/deacetylation has been studied as one of major epigenetic regulatory mechanisms for specific gene expression, we detected the effects of histone deacetylase (HDAC) inhibitor on marker expression and neuroprotection in in vivo AD model mice. We determined the effects of valproic acid (VPA, HDAC inhibitor), on the levels of cytokines, secreted form of APP (sAPP), nerve growth factor (NGF), and cognitive function in Tg6799 AD mice in three different disease stages (1month: pre-symptomatic; 5months: early symptomatic; and 10months: late-symptomatic stages). VPA decreased the mRNA levels of nuclear factor kappaB (NF-κB) and IL-1ß in the plasma of Tg6799 mice compared to vehicle control at 10months of age. VPA increased the protein levels of NGF in the hippocampus of Tg6799 mice at 5 and 10months of age. In addition, VPA decreased escape latencies of Tg6799 mice at 5 and 10months of age in Morris water maze assessment. Taken together, HDAC inhibition is a promising therapeutic target for AD and it needs to be considered in an age-dependent and/or stage-dependent manner.

Chronic traumatic encephalopathy – neuropathology in athletes and war veterans

Objective: The neuropathologic findings of chronic traumatic encephalopathy (CTE) were first described almost 40 years after the first clinical reports. We reviewed the literature and describe the neuropathological findings seen primarily in professional athletes and more recently, in war veterans. Methods: We reviewed the literature of CTE concentrating on references that focused on the correlation of clinical findings with the neuropathologic changes. The pathobiology and proposed mechanisms of injury are described. Diagnostic modalities and various diagnostic criteria of CTE are reviewed. Results: We are beginning to understand the neuropathologic basis of CTE, which appears to be a consequence of repetitive mild brain injuries. There appear to be reproducible criteria for the post-mortem diagnosis of CTE and the neuropathologic findings are becoming more widely accepted. More research is required to elucidate the risk factors that predispose athletes and war veterans to CTE. There is also a need for more diagnostic markers and a method to assess CTE in patients prior to death. The neuropathologic findings of a progressive tauopathy including the presence of numerous neurofibrillary tangles (NFTs), rare neuritic plaques, and widespread expression of TDP-43 (transactive response [TAR] DNA binding protein 43) also require further study. Discussion: The potential prevalence of CTE, as well as the vulnerable populations involved, makes research into this topic crucial. Currently, a comprehensive neurological exam, neuropsychiatric assessment, and standard radiographic techniques such as conventional MRI are the mainstay of diagnosis. There is a pressing need for the prevention of CTE and the development of non-invasive diagnostic tests in order to develop therapies that may be of clinical use to athletes and blast injury veterans during their lifetimes.

Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3xTg-AD mice

In addition to the occurrence of numerous neurofibrillary tangles and Aβ plaques, neurogenesis and neuronal plasticity are markedly altered in Alzheimer disease (AD). Although the most popular therapeutic approach has been to inhibit neurodegeneration, another is to promote neurogenesis and neuronal plasticity by utilizing the regenerative capacity of the brain. Here we show that, in a transgenic mouse model of AD, 3xTg-AD mice, there was a marked deficit in neurogenesis and neuroplasticity, which occurred before the formation of any neurofibrillary tangles or Aβ plaques and was associated with cognitive impairment. Furthermore, peripheral administration of Peptide 6, an 11-mer, which makes an active region of ciliary neurotrophic factor (CNTF, amino acid residues 146-156), restored cognition by enhancing neurogenesis and neuronal plasticity in these mice. Although this treatment had no detectable effect on Aβ and tau pathologies in 9-month animals, it enhanced neurogenesis in dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and cerebral cortex. These findings, for the first time, demonstrate the possibility of therapeutic treatment of AD and related disorders by peripheral administration of a peptide corresponding to a biologically active region of CNTF.

A novel etiopathogenic mechanism and a disease-relevant non-transgenic rat model of Alzheimer's disease

Alzheimer's disease (AD) is pathologically characterized by the presence of numerous intracellular neurofibrillary tangles and extracellular β-amyloid plaques. Development of rational therapeutical treatments of AD requires the elucidation of the mechanisms that lead to tau protein pathology and β-amyloidosis. We employed an adeno-associated virus serotype 1 (AAV1)-induced expression of the C-terminal fragment (I2CTF) of I2PP2A/SET and infected newborn Wistar rat pups by bilateral intracerebroventricular (ICV) injection with the AAV1- I2CTF. I2CTF, tau phosphorylation and neurodegeneration were studied immunohistochemically and by Western blot. The reference memory of the animals was evaluated by a spatial reference memory task in the water maze. The AAV1- I2CTF induced a decrease in brain protein phosphatase 2A (PP2A) activity, abnormal hyperphosphorylation of tau and neurodegeneration. Furthermore, there was an increase in the level of activated glycogen synthase kinase-3β and enhanced expression of intraneuronal Aβ in AAV1-I2CTF animals. Morris Water Maze behavioral test revealed that infection with AAV1-I2CTF induced a spatial reference memory and memory consolidation deficit. Finally, this cognitive impairment was associated with a decrease in the brain level of pSer133-CREB. This findings of this study suggest (1) a novel etiopathogenic mechanism of AD which is initiated by the cleavage of I2PP2A, producing I2CTF and (2) provide a practical, non-transgenic animal model which is based on an etiopathogenic mechanism of AD.

Vascular pathology in Alzheimer's disease

Histopathologically, numerous senile plaques and neurofibrillary tangles were remarkably observed in the brain with Alzheimer's disease. At the same time, so much simple atrophy of nerve cells was evident under light microscopy.Electron microscopical observations of serial sections revealed that small blood vessels, including capillaries, had a deep relationship to the amyloid fibrils which formed the senile plaques and they had fallen into degenerative states. The vascular feet of the astroglial cells surrounding small blood vessels showed degenerative features, and many nerve cells in this area either showed various degrees of degeneration or apparently were destroyed. The atrophy of the brain with Alzheimer's disease is considered to be caused by the amyloid angiopathy of small blood vessels and the degeneration of capillaries and vascular feet. These findings strongly suggest that the major causal mechanism of Alzheimer's disease is an alteration of the blood-brain barrier. Morphology is an expression of both the structure and the function of organs in the living body. Based on this viewpoint, this review article emphasizes that the morphological changes to small blood vessels in the brain with Alzheimer's disease convey crucial information and clues for solving the underlying mechanism that causes the disease.

A peptidyl–prolyl isomerase, FKBP12, accumulates in Alzheimer neurofibrillary tangles

We investigated a possible role in Alzheimer's disease (AD) for FKBP12, a peptidyl–prolyl cis–trans isomerase known to be important in protein assembly, folding and transportation by using Western blotting and microscopic analyses in postmortem brain tissues from elderly controls and the patients with AD. FKBP12 was enriched and localized to neuronal cell bodies and neurites in control brains. Intense immunoreactivity was found in large neurons such as pyramidal cells. Many FKBP12 positive granules were located in the cytoplasm and the proximal portion of dendrites and axons, and in the nuclei. By contrast, the expression of FKBP12 in AD brains was lower than in control brains. Furthermore, numerous intracellular neurofibrillary tangles (NFTs) were stained for FKBP12 in the hippocampal CA1 subfield, subiculum, entorhinal cortex and angular gyrus. Neuritic pathology such as neuropil threads and dystrophic neurites (DNs) within senile plaques (SPs) and some reactive astrocytes were also immunolabeled for FKBP12 in AD. Double immunofluorescence staining showed dual labeling of intracellular NFTs for FKBP12 and tau. Similar results were obtained in reactive astrocytes for the combination of FKBP12 and glial fibrillary acidic protein (GFAP). Labeling for FKBP12 was dense in axons stained for highly phosphorylated neurofilament protein. Thus our results suggest that FKBP12 may be involved in neuronal or astrocytic cytoskeletal organization and in the abnormal metabolism of tau protein in AD damaged neurons.

Hyperhomocysteinemia Increases β-Amyloid by Enhancing Expression of γ-Secretase and Phosphorylation of Amyloid Precursor Protein in Rat Brain

Hyperhomocysteinemia and beta-amyloid (Abeta) overproduction are critical etiological and pathological factors in Alzheimer disease, respectively; however, the intrinsic link between them is still missing. Here, we found that Abeta levels increased and amyloid precursor protein (APP) levels simultaneously decreased in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine. Concurrently, both the mRNA and protein levels of presenilin-1, a component of gamma-secretase, were elevated, whereas the expression levels of beta-secretase and presenilin-2 were not altered. We also observed that levels of phosphorylated APP at threonine-668, a crucial site facilitating the amyloidogenic cleavage of APP, increased in rats with hyperhomocysteinemia, although the phosphorylation per se did not increase the binding capacity of pT668-APP to the secretases. The enhanced phosphorylation of APP in these rats was not relevant to either c-Jun N-terminal kinase or cyclin-dependent kinase-5. A prominent spatial memory deficit was detected in rats with hyperhomocysteinemia. Simultaneous supplementation of folate and vitamin-B12 attenuated the hyperhomocysteinemia-induced abnormal processing of APP and improved memory. Our data revealed that hyperhomocysteinemia could increase Abeta production through the enhanced expression of gamma-secretase and APP phosphorylation, causing memory deficits that could be rescued by folate and vitamin-B12 treatment in these rats. It is suggested that hyperhomocysteinemia may serve as an upstream factor for increased Abeta production as seen in patients with Alzheimer disease.

Cerebral amyloid angiopathy-related hemorrhage in a middle-aged patient with Down's syndrome

A patient with Down's syndrome (DS) died of cerebral hemorrhage at age 52. At autopsy, a large sub-cortical hematoma was present in the right frontal lobe, and microscopic examination showed numerous senile plaques and neurofibrillary tangles in an extensive area of neocortex and also disclosed heavy involvement of vascular walls by amyloid deposition. These senile plaque and vascular amyloid deposits were specifically stained with an antibody to Aβ. His APOE genotype was ϵ4/ϵ4. This is a rare case of DS with cerebral amyloid angiopathy (CAA)-related cerebral hemorrhage. Genetic factors, such as APOE genotype, conceivably determine the risk of vascular rupture in individuals with CAA, even among patients with DS.

Dementia Pugilistica with clinical features of Alzheimer's disease

A 61-year-old ex-boxer presented with a three-year history of progressive memory decline. During a seven-year follow-up period, there was a continuous cognitive decline, very similar to that usually observed in Alzheimer's disease. Parkinsonian, pyramidal or cerebellar signs were conspicuously absent. Neuropathological examination revealed the typical features of dementia pugilistica: cavum septi pellucidi with multiple fenestrations, numerous neurofibrillary tangles in the cerebral isocortex and hippocampus (and rare senile plaques). Immunohistochemistry disclosed a high number of tau protein deposits and scarce beta-amyloid staining. This case shows that dementia pugilistica may present with clinical features practically undistinguishable from Alzheimer's disease.

O2-01-06: Inhibition of more than one tau kinase might be required for prevention of Alzheimer disease

Alzheimer disease (AD) is characterized clinically by progressive dementia and histopathologically by the presence of numerous neurofibrillary tangles and neuritic (senile) plaques in the neocortex, especially the hippocampus. However, AD is multifactorial and heterogeneous and most likely involves several etiopathogenic mechanisms. Development of rational diagnostic tests and therapeutic drugs for AD will require understanding of the various etiopathogenic mechanisms involved. Here we show that more than one combination of proteinkinases can be involved in producing AD-type neurofibrillary pathology. Abnormally hyperphosphorylated tau was isolated from AD brain cytosol (AD P-tau), and its ability to inhibit microtubule assembly and self-assembly into filaments was studied before and after dephosphorylation with protein phosphatase-2A (PP-2A), and after rephosphorylation by several combinations of tau kinases. We found that dephosphorylation of AD P-tau by PP-2A converts it into a normal-like protein and on rephosphorylation by PKA, cdk5 and GSK-3β or cdk5 or cdk5 plus GSK-3β, converts it back into an AD-type pathological protein. Investigation of site-specific phosphorylation revealed that phosphorylation of tau at Thr231 and Ser262 plays a pivotal role in its conversion into AD-like pathological protein. More than one etiopathogenic mechanism might be involved in AD-type neurofibrillary degeneration, and inhibition of more than one tau kinase might be required to inhibit neurofibrillary degeneration. Supported in part by the New York State Office of Mental Retardation and Developmental Disabilities, NIH Grant AG019158 and Alzheimer's Association grant IIRG-06–25836.

Quantitative analysis of neurofibrillary pathology in a general population to reappraise neuropathological criteria for senile dementia of the neurofibrillary tangle type (tangle‐only dementia): The Hisayama study

Senile dementia of the neurofibrillary tangle type (SD-NFT) is characterized by numerous neurofibrillary tangles (NFT) in the hippocampal region and the absence or minimal presence of senile plaques throughout the brain. We analyzed 207 demented subjects and 68 non-demented subjects autopsied in the Hisayama study to investigate the clinicopathological aspects of SD-NFF in the general Japanese population. The prevalence of SD-NFT in the consecutive autopsy cases was 8/207 (3.9%), comprising three men and five women. The average age at onset and death was 83.8 +/- 6.8 (mean +/- SD; standard deviation) and 88.1 +/- 7.6 years, respectively. A mild memory disturbance preceded a decrease in the ability to undertake the activities of daily living and the diagnosis of dementia. Focal cerebral symptoms, such as aphasia and paralysis, did not appear during the disease course of any subject. Gross examination of the brains showed moderate to severe diffuse cerebral atrophy with brain weight loss (mean +/- SD; standard deviation: 1118.1 +/- 124.0 g). Histologically, there were abundant NFT and neuropil threads predominantly in or limited to the limbic cortex. The density of NFT in the CA1/subiculum in SD-NFT was much higher than the densities in the other hippocampal regions. The average density of NFT in CA1 in SD-NFT subjects was 115.4 per 100 x field (range 23-247), that in Alzheimer disease (AD) subjects was 80.1 (range 1-227), and that in non-demented elderly subjects was 37.2 (range 0-203). Although many previous papers have reported that the densities of NFT in the limbic system in SD-NFT were significantly higher than those in AD, there was considerable overlap of NFT densities in CA1 among the non-demented elderly, AD subjects and SD-NFT subjects.

Immunohistochemical investigation of neurofibrillary tangles and their tau isoforms in brains of limbic neurofibrillary tangle dementia

Limbic neurofibrillary tangle dementia (LNTD) is a subset of senile dementia characterized by numerous neurofibrillary tangles (NFT) in the hippocampal area, although there is an absence or scarcity of amyloid deposits (AM) throughout the brain. In the present study, we immunohistochemically investigated regional numbers and tau isoforms of NFT in the hippocampal area of nine LNTD patients with anti-three-repeat (3R) tau-specific and anti-four-repeat (4R) tau-specific antibodies, differentiating NFT into three developmental stages of pretangles (PT), NFT and ghost tangles (GT). Consequently, most PT were 4R tau-positive, most GT were 3R tau-positive, and NFT were 3R tau-, 4R tau- or double-positive, suggesting that composition of tau isoforms may shift from a 4R tau-predominant pattern to a 3R tau-predominant pattern during the development of NFT. In addition, a large number of NFT showing different developmental stages and different rates of 3R tau- and 4R tau-positive neurons according to the region were found in the hippocampal area, suggesting that regions undergoing earlier NFT formation may show higher ratio of 3R tau-positive neurons to 4R tau-positive neurons, and that NFT formation may begin in the entorhinal and transentorhinal cortices, subsequently progress to the subiculum and CA1, and further to the CA2, amygdala and CA3–4, although progression to the neocortex is limited. Furthermore, 4R tau-positive astrocytes and grains were found in several patients, suggesting that LNTD is a form of tauopathy.

Glial fibrillary tangles in diffuse neurofibrillary tangles with calcification.

In the present study the occurrence and distribution of glial fibrillary tangles (GFT) and their related structures in diffuse neurofibrillary tangles with calcification (DNTC) were investigated using Gallyas-Braak (GB) stain. Six cases neuropathologically diagnosed as DNTC were studied (two males and four females). The age at death ranged from 56 to 73 years, with an average of 63.5+/-7.5 years. GFT were classified morphologically, and their immunoreactivites for tau and ubiquitin were examined. Glial cells with GFT were identified with astrocytes and oligodendrocytes by immunostain for glial fibrillary acidic protein and transferrin, respectively. A small number of coiled bodies detected within the oligodendrocytes in the white matter of the cerebrum were positive for tau and ubiquitin. Cell clusters of thorn-shaped astrocytes were detected in the subcortical and subpial regions where gliosis occurred. Thorn-shaped astrocytes were positive for tau, but negative for ubiquitin. A small number of tuft-shaped astrocytes detected prominently in the temporal cortex and amygdala with numerous neurofibrillary tangles were positive for tau and ubiquitin. All three types of GFT were detected, especially in the temporal and limbic lobes, which were the most severely affected sites in DNTC. Moreover, various-shaped neurofibrillary tangles, aggregated rods and some argyrophilic threads were differentiated from GFT. They were positive for GB, but not detected within the glial cells.