ABSTRACT
We report a patient with behavioral variant frontotemporal dementia who developed agraphia, irritability, perseverative and stereotyped behavior, and dietary changes. MRI revealed bilateral frontal convexity atrophy. Neuropsychological examination showed fluent aphasia with perseverative allographic agraphia, mild semantic impairment, and dysexecutive syndrome. Allographic agraphia featured unidirectional conversion from hiragana (cursive form of Japanese phonograms) and kanji (Japanese morphograms) to katakana (square form of Japanese phonograms), as opposed to mutual (bidirectional) conversion between hiragana and katakana in parieto-occipital gyri lesions. Furthermore, all letters of the word were converted and this whole-word conversion may be characteristic of perseverative behavior in frontotemporal dementia.
Subject(s)
Agraphia , Frontotemporal Dementia , Humans , Frontotemporal Dementia/pathology , Frontotemporal Dementia/diagnostic imaging , Frontotemporal Dementia/physiopathology , Frontotemporal Dementia/complications , Agraphia/etiology , Agraphia/physiopathology , Male , Magnetic Resonance Imaging , Middle Aged , Neuropsychological Tests , Frontal Lobe/diagnostic imaging , Frontal Lobe/pathology , Atrophy/pathologyABSTRACT
A 73-year-old woman with posterior cortical atrophy (PCA) presented with progressive apperceptive visual agnosia, alexia, agraphia, ventral simultanagnosia, prosopagnosia, and allocentric (stimulus-centered) left-sided hemispatial neglect. All of these symptoms were attributed to damage to the bilateral occipito-temporal cortices, consistent with ventral variant PCA. While the Pittsburgh compound B uptake was extensively distributed throughout the occipito-parietal (dorsal) and occipito-temporal (ventral) areas, the THK5351 (ligand binding to tau aggregates/astrocyte gliosis) accumulation was limited to the ventral area. These findings suggest that local accumulation of tau proteins and/or astrocyte gliosis over the occipito-temporal cortices can result in ventral variant PCA.
ABSTRACT
We herein report a 45-year-old man with dentatorubropallidoluysian atrophy (DRPLA) who presented with mild dementia, ataxia, and involuntary movement and developed constipation, dysuria, and orthostatic hypotension. Thermography revealed an abnormal thermal response of the skin to cold stimulation. Skin temperature reflects the skin blood flow and is regulated by the sympathetic nervous system. Thermography is currently used to study diseases associated with vasomotor dysfunction of the skin. The thermography results suggested the possibility of autonomic dysfunction. Although little is known regarding autonomic dysfunction in DRPLA, this report demonstrates the importance of autonomic dysfunction in DRPLA.
Subject(s)
Autonomic Nervous System Diseases , Cerebellar Ataxia , Dementia , Male , Humans , Middle Aged , Autonomic Nervous System Diseases/complications , Autonomic Nervous System Diseases/diagnosis , Ataxia , AtrophyABSTRACT
The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer's disease. While this mutation accelerates amyloid ß (Aß) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aß oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aß accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aß oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aß accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Disease Models, Animal , gamma-Aminobutyric Acid/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Animals , Brain/drug effects , Brain/metabolism , Brain/pathology , Diazepam/pharmacology , GABA Modulators/pharmacology , GABAergic Neurons/drug effects , GABAergic Neurons/metabolism , GABAergic Neurons/pathology , Gene Knock-In Techniques , Genes, Recessive , Genetic Predisposition to Disease , Humans , Male , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Transgenic , Mutation , Spatial Memory/drug effects , Spatial Memory/physiology , Tissue Culture Techniques , tau Proteins/metabolismABSTRACT
Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72 Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.
Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Proto-Oncogene Proteins c-abl/metabolism , Proto-Oncogene Proteins pp60(c-src)/metabolism , Humans , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Motor Neurons/cytology , Motor Neurons/metabolism , Mutation/genetics , Proto-Oncogene Proteins c-abl/genetics , Proto-Oncogene Proteins pp60(c-src)/genetics , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolismSubject(s)
Arteritis/complications , Circle of Willis/immunology , Nerve Compression Syndromes/complications , Oculomotor Nerve Diseases/etiology , Oculomotor Nerve , Adult , Arteritis/diagnostic imaging , Arteritis/drug therapy , Circle of Willis/diagnostic imaging , Circle of Willis/drug effects , Female , Humans , Male , Middle Aged , Nerve Compression Syndromes/diagnostic imaging , Nerve Compression Syndromes/drug therapy , Oculomotor Nerve/diagnostic imaging , Oculomotor Nerve/drug effects , Oculomotor Nerve Diseases/diagnostic imaging , Oculomotor Nerve Diseases/drug therapyABSTRACT
INTRODUCTION: An increasing number of adult patients have been diagnosed with fatty acid ß-oxidation disorders with the rising use of diagnostic technologies. In this study, clinical, biochemical, and molecular characteristics of 2 Japanese patients with adult-onset glutaric acidemia type II (GA2) were investigated and compared with those of pediatric cases. METHODS: The patients were a 58-year-old male and a 31-year-old male. In both cases, episodes of myopathic symptoms, including myalgia, muscle weakness, and liver dysfunction of unknown cause, had been noted for the past several years. Muscle biopsy, urinary organic acid analysis (OA), acylcarnitine (AC) analysis in dried blood spots (DBS) and serum, immunoblotting, genetic analysis, and an in vitro probe acylcarnitine (IVP) assay were used for diagnosis and investigation. RESULTS: In both cases, there was no obvious abnormality of AC in DBS or urinary OA, although there was a increase in medium- and long-chain ACs in serum; also, fat deposits were observed in the muscle biopsy. Immunoblotting and gene analysis revealed that both patients had GA2 due to a defect in electron transfer flavoprotein dehydrogenase (ETFDH). The IVP assay indicated no special abnormalities in either case. CONCLUSION: Late-onset GA2 is separated into the intermediate and myopathic forms. In the myopathic form, episodic muscular symptoms or liver dysfunction are primarily exhibited after later childhood. Muscle biopsy and serum (or plasma) AC analysis allow accurate diagnosis in contrast with other biochemical tests, such as analysis of AC in DBS, urinary OA, or the IVP assay, which show fewer abnormalities in the myopathic form compared to intermediate form.
Subject(s)
Multiple Acyl Coenzyme A Dehydrogenase Deficiency/metabolism , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/pathology , Adult , Age Factors , Carnitine/analogs & derivatives , Carnitine/blood , Humans , Male , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/blood , Muscle Weakness/blood , Muscle Weakness/pathology , Muscular Diseases/blood , Muscular Diseases/pathologySubject(s)
Bezafibrate/therapeutic use , Carnitine/analogs & derivatives , Carnitine/therapeutic use , Electron-Transferring Flavoproteins/genetics , Hypolipidemic Agents/therapeutic use , Iron-Sulfur Proteins/genetics , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/drug therapy , Oxidoreductases Acting on CH-NH Group Donors/genetics , Riboflavin/therapeutic use , Adult , Carnitine/blood , Drug Therapy, Combination , Humans , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/blood , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/genetics , Mutation , Treatment OutcomeABSTRACT
A 52-year-old Japanese woman complaining of horizontal double vision for 10 days was admitted to our hospital. Neurological examination revealed left abducent nerve palsy and muscle swelling in her thighs. Brain MRI showed obstruction in the spinal fluid space of the left Dorello's canal, which transmits a portion of the abducent nerve. In Ga-67-enhanced citrate scintigraphy, wide accumulation was seen in her bilateral thighs, lower legs, and gluteus muscles. Muscular MRI showed a star-shaped central structure on short tau inversion recovery (STIR) images, and the three stripes sign on T2-weighted images. These MRI findings indicated nodular-type muscular sarcoidosis. A muscle biopsy from the quadriceps femoris showed granulomatous epithelioid giant cells and non-necrotizing chronic lymphadenitis, which also indicate sarcoidosis. Her condition was considered to be caused by sarcoid granulomas obstructing Dorello's canal. She was treated with oral prednisolone (1 mg·kg(-1)·day(-1)) and her symptoms and MRI findings improved. This is the first known report of abducent nerve impairment in Dorello's canal, other than fetal hypoplasia. Brain MRI, muscular MRI, and muscle biopsy are useful for the diagnosis of abducent nerve palsy, and it is important to consider Dorello's canal obstruction by sarcoidosis. Complete remission can be achieved with proper treatment.
Subject(s)
Abducens Nerve Diseases/complications , Muscular Diseases/complications , Sarcoidosis/complications , Abducens Nerve/physiopathology , Brain/pathology , Female , Humans , Magnetic Resonance Imaging , Middle Aged , Muscle, Skeletal/pathologyABSTRACT
The hallmark of Alzheimer's disease (AD) pathology is an accumulation of amyloid ß (Aß) and phosphorylated tau, which are encoded by the amyloid precursor protein (APP) and microtubule-associated protein tau (MAPT) genes, respectively. Less than 5% of all AD cases are familial in nature, i.e. caused by mutations in APP, PSEN1 or PSEN2. Almost all mutations found in them are related to an overproduction of Aß1-42, which is prone to aggregation. While these genes are mutation free, their function, or those of related genes, could be compromised in sporadic AD as well. In this study, pyrosequencing analysis of post-mortem brains revealed aberrant CpG methylation in APP, MAPT and GSK3B genes of the AD brain. These changes were further evaluated by a newly developed in vitro-specific DNA methylation system, which in turn highlighted an enhanced expression of APP and MAPT. Cell nucleus sorting of post-mortem brains revealed that the methylation changes of APP and MAPT occurred in both neuronal and non-neuronal cells, whereas GSK3B was abnormally methylated in non-neuronal cells. Further analysis revealed an association between abnormal APP CpG methylation and apolipoprotein E ε4 allele (APOE ε4)-negative cases. The presence of a small number of highly methylated neurons among normal neurons contribute to the methylation difference in APP and MAPT CpGs, thus abnormally methylated cells could compromise the neural circuit and/or serve as 'seed cells' for abnormal protein propagation. Our results provide a link between familial AD genes and sporadic neuropathology, thus emphasizing an epigenetic pathomechanism for sporadic AD.
Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , CpG Islands , DNA Methylation , tau Proteins/genetics , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/metabolism , Apolipoprotein E4/genetics , Apolipoprotein E4/metabolism , Brain/metabolism , Brain/pathology , Case-Control Studies , Cell Nucleus/genetics , Epigenesis, Genetic , Female , Glycogen Synthase Kinase 3/genetics , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Male , Neurons/pathology , Neurons/physiology , tau Proteins/metabolismABSTRACT
TDP-43 is a discriminative protein that is found as intracellular aggregations in the neurons of the cerebral cortex and spinal cord of patients with amyotrophic lateral sclerosis (ALS); however, the mechanisms of neuron loss and its relation to the aggregations are still unclear. In this study, we generated a useful model to produce TDP-43 aggregations in the motor cortex using in utero electroporation on mouse embryos. The plasmids used were full-length TDP-43 and C-terminal fragments of TDP-43 (wild-type or M337V mutant) tagged with GFP. For the full-length TDP-43, both wild-type and mutant, electroporated TDP-43 localized mostly in the nucleus, and though aggregations were detected in embryonic brains, they were very rarely observed at P7 and P21. In contrast, TDP-43 aggregations were generated in the brains electroporated with the C-terminal TDP-43 fragments as previously reported in in vitro experiments. TDP-43 protein was distributed diffusely-not only in the nucleus, but also in the cytoplasm-and the inclusion bodies were ubiquitinated and included phosphorylated TDP-43, which reflects the human pathology of ALS. This model using in utero electroporation of pathogenic genes into the brain of the mouse will likely become a useful model for studying ALS and also for evaluation of agents for therapeutic purpose, and may be applicable to other neurodegenerative diseases, as well.
Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , DNA-Binding Proteins/metabolism , Disease Models, Animal , Motor Cortex/metabolism , Amyotrophic Lateral Sclerosis/embryology , Animals , Electroporation , Female , HEK293 Cells , Humans , Mice , Mice, Inbred ICR , Motor Cortex/embryology , PregnancyABSTRACT
Our work and the study of Bilican et al. highlight the need for complementary assays to detect subtle phenotypic differences between control and mutant induced pluripotent stem cell lines.
Subject(s)
Amyotrophic Lateral Sclerosis/pathology , Drug Evaluation, Preclinical/methods , Induced Pluripotent Stem Cells/cytology , Motor Neurons/cytology , HumansABSTRACT
Spinocerebellar ataxia autosomal recessive 1 (SCAR1/AOA2) is clinically characterized by an early-onset progressive cerebellar ataxia with axonal neuropathy, ocular motor apraxia, and elevation of serum alpha-fetoprotein level. The disorder is caused by mutations in senataxin (SETX) gene. Here, we report a Japanese SCAR1/AOA2 family with a homozygous nonsense mutation (p.Q1441X) of SETX that was identified by exome sequencing. The family was previously reported as early-onset ataxia of undetermined cause. The present study emphasized the role of whole exome-sequence analysis to establish the molecular diagnosis of neurodegenerative disease presenting with diverse clinical presentations.
Subject(s)
Exome/genetics , Family Health , Polymorphism, Single Nucleotide/genetics , RNA Helicases/genetics , Spinocerebellar Degenerations/genetics , DNA Helicases , DNA Mutational Analysis , Female , Genetic Linkage , Humans , Japan , Male , Multifunctional Enzymes , Spinocerebellar Ataxias/congenitalABSTRACT
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a neurodegenerative disorder caused by mutations in the tau gene. Many mutations identified in FTDP-17 have been shown to affect tau exon 10 splicing in vitro, which presumably causes pathologic imbalances in exon 10(-) [3-repeat (3R)] and exon 10(+) [4-repeat (4R)] tau expression and leads to intracellular inclusions of hyperphosphorylated tau in patient brains. However, no reports have investigated this theory using model mice with a tau intronic mutation. Herein, we generated new transgenic mice harboring the tau intron 10 +16C â T mutation. We prepared a transgene construct containing intronic sequences required for exon 10 splicing in the longest tau isoform cDNA. Although mice bearing the construct without the intronic mutation showed normal developmental changes of the tau isoform from 3R tau to equal amounts of 3R and 4R tau, mice with the mutation showed much higher levels of 4R tau at the adult stage. 4R tau was selectively recovered in insoluble brain fractions in their old age. Furthermore, these mice displayed abnormal tau phosphorylation, synapse loss and dysfunction, memory impairment, glial activation, tangle formation, and neuronal loss in an age-dependent manner. These findings provide the first evidence in a mouse model that a tau intronic mutation-induced imbalance of 3R and 4R tau could be a cause of tauopathy.
Subject(s)
Exons , Frontotemporal Dementia/genetics , Introns , Mutation , RNA Splicing , Tauopathies/genetics , tau Proteins/genetics , Animals , Blotting, Western , Frontotemporal Dementia/pathology , Frontotemporal Dementia/physiopathology , Genetic Markers , Male , Mice , Mice, Transgenic , Reverse Transcriptase Polymerase Chain Reaction , Tauopathies/pathology , Tauopathies/physiopathologyABSTRACT
By reviewing and collating data in a 2-step postal survey sent to all of the institutions for individuals with dementia in Ibaraki prefecture requesting information on early-onset dementia (EOD) cases, 617 subjects with EOD were identified. The estimated prevalence of EOD in the target population was 42.3 per 100,000. Of the illness causing EOD, vascular dementia was the most frequent followed by Alzheimer's disease, head trauma, dementia with Lewy body/Parkinson's disease with dementia, frontotemporal lobar degeneration, and other causes. On the other hand, hereditary diffuse leucoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white matter disease with variable phenotypes. The onset of symptoms is usually in the fourth or fifth decade, progressing to dementia with death within 6 years. Recently, several mutations of the colony stimulating factor 1 receptor encoded by CSF1R segregating HDLS were identified. Since clinical presentations varied substantially within and across families with HDLS, CSF1R mutation carriers may be present in clinical series of Alzheimer's disease, frontotemporal lobar degeneration, corticobasal syndrome, multiple sclerosis, CADASIL, Parkinson's disease and ischemic stroke with additional white matter changes, all causing EOD. In the differential diagnosis of EOD, we should always consider HDLS and if necessary perform CSF1R gene analysis.
Subject(s)
Dementia/complications , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Alzheimer Disease/complications , Female , Humans , Leukoencephalopathies/complications , Male , Middle AgedABSTRACT
We herein report a case of ocular myasthenia gravis (MG) that was highly positive for anti-muscle-specific tyrosine kinase (MuSK) antibodies. The examined patient exhibited bilateral ptosis and lateral gaze palsy without any generalized symptoms and was diagnosed with ocular MG with anti-MuSK antibodies. She responded to treatment with prednisolone and immunosuppressants and experienced only ocular symptoms for four years and eight months after onset. Ocular MG with anti-MuSK antibodies lasting for a long term has rarely been described. Our findings suggest that it may be reasonable to test for the presence of anti-MuSK antibodies in patients who present with external ophthalmoplegia.
Subject(s)
Autoantibodies/blood , Eye Diseases/immunology , Myasthenia Gravis/immunology , Receptor Protein-Tyrosine Kinases/immunology , Receptors, Cholinergic/immunology , Adult , Eye Diseases/complications , Eye Diseases/diagnosis , Eye Diseases/enzymology , Female , Humans , Myasthenia Gravis/complications , Myasthenia Gravis/diagnosis , Myasthenia Gravis/enzymology , Ophthalmoplegia/etiology , Ophthalmoplegia/immunology , Time FactorsABSTRACT
Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which the motor neurons degenerate. The discovery of new drugs for treating ALS has been hampered by a lack of access to motor neurons from ALS patients and appropriate disease models. We generate motor neurons from induced pluripotent stem cells (iPSCs) from familial ALS patients, who carry mutations in Tar DNA binding protein-43 (TDP-43). ALS patient-specific iPSC-derived motor neurons formed cytosolic aggregates similar to those seen in postmortem tissue from ALS patients and exhibited shorter neurites as seen in a zebrafish model of ALS. The ALS motor neurons were characterized by increased mutant TDP-43 protein in a detergent-insoluble form bound to a spliceosomal factor SNRPB2. Expression array analyses detected small increases in the expression of genes involved in RNA metabolism and decreases in the expression of genes encoding cytoskeletal proteins. We examined four chemical compounds and found that a histone acetyltransferase inhibitor called anacardic acid rescued the abnormal ALS motor neuron phenotype. These findings suggest that motor neurons generated from ALS patient-derived iPSCs may provide a useful tool for elucidating ALS disease pathogenesis and for screening drug candidates.
Subject(s)
Amyotrophic Lateral Sclerosis/pathology , Drug Evaluation, Preclinical/methods , Induced Pluripotent Stem Cells/cytology , Motor Neurons/cytology , Amyotrophic Lateral Sclerosis/metabolism , Cell Differentiation , Cells, Cultured , Humans , Immunoprecipitation , Induced Pluripotent Stem Cells/metabolism , Motor Neurons/metabolismABSTRACT
BACKGROUND: Alpha-synuclein (SNCA) gene expression is an important factor in the pathogenesis of Parkinson's disease (PD). Gene multiplication can cause inherited PD, and promoter polymorphisms that increase SNCA expression are associated with sporadic PD. CpG methylation in the promoter region may also influence SNCA expression. METHODOLOGY/PRINCIPAL FINDINGS: By using cultured cells, we identified a region of the SNCA CpG island in which the methylation status altered along with increased SNCA expression. Postmortem brain analysis revealed regional non-specific methylation differences in this CpG region in the anterior cingulate and putamen among controls and PD; however, in the substantia nigra of PD, methylation was significantly decreased. CONCLUSIONS/SIGNIFICANCE: This CpG region may function as an intronic regulatory element for SNCA gene. Our findings suggest that a novel epigenetic regulatory mechanism controlling SNCA expression influences PD pathogenesis.
Subject(s)
CpG Islands/genetics , DNA Methylation , Parkinson Disease/genetics , alpha-Synuclein/genetics , Aged , Aged, 80 and over , Animals , Dopamine/pharmacology , Female , Gene Expression Regulation/drug effects , Genetic Predisposition to Disease , HEK293 Cells , HeLa Cells , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Parkinson Disease/metabolism , Parkinson Disease/pathology , Postmortem Changes , alpha-Synuclein/metabolismABSTRACT
Although amyloid beta (Abeta) oligomers are presumed to cause synaptic and cognitive dysfunction in Alzheimer's disease (AD), their contribution to other pathological features of AD remains unclear. To address the latter, we generated APP transgenic mice expressing the E693Delta mutation, which causes AD by enhanced Abeta oligomerization without fibrillization. The mice displayed age-dependent accumulation of intraneuronal Abeta oligomers from 8 months but no extracellular amyloid deposits even at 24 months. Hippocampal synaptic plasticity and memory were impaired at 8 months, at which time the presynaptic marker synaptophysin began to decrease. Furthermore, we detected abnormal tau phosphorylation from 8 months, microglial activation from 12 months, astrocyte activation from 18 months, and neuronal loss at 24 months. These findings suggest that Abeta oligomers cause not only synaptic alteration but also other features of AD pathology and that these mice are a useful model of Abeta oligomer-induced pathology in the absence of amyloid plaques.