Hanae Nakashima

Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies

Lithium, a widely used drug for treating affective disorders, is known to inhibit glycogen synthase kinase-3 (GSK-3), which is one of the major tau kinases. Thus, lithium could have therapeutic benefit in neurodegenerative tauopathies by reducing tau hyperphosphorylation. We tested this hypothesis and showed that long-term administration of lithium at relatively low therapeutic concentrations to transgenic mice that recapitulate Alzheimer’s disease (AD)-like tau pathologies reduces tau lesions, primarily by promoting their ubiquitination rather than by inhibiting tau phosphorylation. These findings suggest novel mechanisms whereby lithium treatment could ameliorate tauopathies including AD. Because lithium also has been shown to reduce the burden of amyloid-β pathologies, it is plausible that lithium could reduce the formation of both amyloid plaques and tau tangles, the two pathological hallmarks of AD, and thereby ameliorate the behavioral deficits in AD.

Frequency of early and late-onset dementias in a Japanese memory disorders clinic

The aim of this study was to compare the diagnostic profiles of patients with early (age <65 years) and late (age ≥65 years) onset of dementia in a memory disorders clinic in Japan. A total of 512 consecutive memory clinic patients were evaluated using clinical information and results of examinations. Diagnosis of dementia was made according to DSM‐III‐R, and that of subtypes according to standard diagnostic criteria. A total of 464 patients met the criteria for dementia. Amongst late‐onset patients (n = 430), Alzheimers disease (AD) (48.1%) was the most frequent cause of dementia, followed by AD with cerebrovascular disease (CVD) (31.4%), vascular dementia (VaD) (9.1%), dementia with Lewy bodies (DLB) (3.7%), frontotemporal lobar degeneration (FTLD) (1.6%), and others (5.8%). On the contrary, amongst early onset patients (n = 34), the most common dementia diagnosis was AD (38.2%), followed by VaD (23.5%), FTLD (14.7%), AD with CVD (5.9%), DLB (2.9%), and others (17.6%). FTLD and VaD were significantly more common in the early onset group. All patients, but one, with DLB and Parkinsons disease dementia were late‐onset. The relative frequencies of AD, VaD, and DLB in our series are consistent with epidemiologic findings in several Western countries; however, the frequency of FTLD is not consistent with the previous findings presenting high frequency in late‐onset patients in some Western countries.

Amyloid precursor protein cytoplasmic domain with phospho-Thr668 accumulates in Alzheimer’s disease and its transgenic models: a role to mediate interaction of Aβ and tau

Abnormal accumulation of Aβ and tau in senile plaques (SP) and neurofibrillary tangles (NFTs) is a key event in Alzheimer’s disease (AD). Here, we show that T668-phosphorylated cytoplasmic domain of APP (pT668-ACD) accumulates Aβ and tau in AD and its transgenic models. Anti-pT668 immunostaining of AD brain sections with hydrated autoclave enhancement identified SP neurites and NFTs in which pT668-ACD colocalizes with tau. We produced and examined transgenic (Tg) mice that overexpress human APP695, harboring the double Swedish/London mutation, and develop age-dependently Aβ plaques in the brain. All Aβ plaques contain co-accumulations of pT668-ACD, but co-accumulation of tau appears in only a fraction of Aβ plaques in older animals. We also examined the established tau Tg mice that overexpress the smallest human brain tau isoform and develop neuronal accumulations of tau in older animals. Examination of the old tau Tg mice showed that neuronal cells affected by tau accumulation induce co-accumulation of pT668-ACD. We speculate that in AD brains, extracellular Aβ deposition is accompanied by intracellular accumulation of pT668-ACD, followed by tau accumulation in the SP with dystrophic neurites and that neuronal cells affected by tau accumulation induce co-accumulation of pT668-ACD in NFTs. Thus, pT668-ACD is likely to mediate pathological interaction between Aβ and tau.

Glial involvement in diffuse Lewy body disease.

Abstract. Diffuse Lewy body disease (DLBD) is characterized by the presence of Lewy bodies (LB) in the neurons and neurites of cortical, subcortical, and brain stem structures. Recently, α-synuclein (αS) has been found to be a central constituent of LB. In DLBD, abnormal accumulation of αS has been reported in both neurons and glia, but studies on glial lesions in DLBD have been limited. We examined in detail the constituents and distribution of glial lesions in eight patients with DLBD and report the pathogenesis of the glial lesions. αS-positive neuronal cytoplasmic inclusions (NI), neuropil threads (NT), and coiled bodies (CB) showed similar immunostaining profiles. Without pretreatment, NI, NT, and CB were detected by all antibodies against αS. The immunostaining profile of star-like astrocytes (SLA) was quite different from those of NI, NT, and CB. A few SLA were stained by an antibody against the non-Aβ component portion of αS without pretreatment, but formic acid pretreatment dramatically enhanced SLA immunoreactivity. SLA and CB were found in all eight brains with DLBD. SLA were scarce in the brain stem, but there were hundreds of SLA per visual field at ×100 magnification in the temporal cortex of most cases, while CB were found diffusely in both the cerebral cortex and brain stem, similar to NI. This suggests that the pathogenesis of SLA is different from those of NI and CB.

NACP/α-Synuclein, NAC, and β-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation: a clinicopathological study of two autopsy cases

Abstract. Approximately 60% of familial and sporadic Alzheimers disease (AD) cases manifest Lewy bodies (LBs), of which a major component is α-synuclein. Although the pathogenic role of α-synuclein in AD remains unclear, LB formation might be associated with pathological β-amyloid (Aβ) overproduction. Here, we present the clinical and pathological characteristics of two affected family members from a pedigree with the E184D mutation of presenilin-1. One case presented with typical clinical features of AD, but the other case also developed clinical characteristics of dementia with Lewy bodies (DLB), including visual hallucinations, delusions, and parkinsonism. In both cases, neuropathological examination revealed numerous neurofibrillary tangles and severe Aβ deposition in senile plaques and amyloid angiopathy, in which Aβ42 rather than Aβ40 was predominant. Furthermore, remarkable α-synuclein pathology, including LBs and the accumulation of the non-Aβ component of AD amyloid (NAC) in plaques and astrocytes, was detected only in the case that presented with the symptoms of DLB. These findings suggest that (1) LB pathology can influence the clinical features of familial AD, (2) the E184D mutation of presenilin-1 may be associated with the LB formation through Aβ overproduction, although the process of LB formation is strongly affected by other unknown mechanisms, (3) in neurodegenerative disorders with LBs, there is a common pathophysiological background inducing NAC accumulation in neuritic plaques and astrocytes, and (4) the NAC accumulation in neuritic plaques is modulated by the abnormally aggregated tau protein.

Neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, in the hippocampus of patients with schizophrenia

Several types of evidence suggesting that the inflammatory response system is associated with pathophysiology of schizophrenia have been accumulated. Recently, a prospective double-blind study demonstrated that supplementary treatment with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, produced significantly greater improvement in scores on the Positive and Negative Syndrome Scale (PANSS) and on all subscales during the acute phase in patients with schizophrenia compared with risperidone alone therapy. The therapeutic effect of celecoxib on the psychopathology of schizophrenia is speculated to be based on COX activity inhibition; however, the detailed pharmacological mechanisms are unclear. To clarify whether or not COX-2 expression is altered in schizophrenia, we examined neuronal COX-2 expression in the hippocampus from cases of schizophrenia (n = 17), normal controls (n = 22), and cases of Alzheimers disease (AD) as a positive control (n = 17). Quantitative immunohistochemical analysis demonstrated that neuronal COX-2 expression was significantly up-regulated in each CA1-4 region in Alzheimers disease compared with controls, and that the mean COX-2 immunointensity in CA1-4 was significantly correlated with Abeta load in cases of Alzheimers disease. In contrast, COX-2 expression was not up-regulated in any subdivision of the hippocampus in the schizophrenia group. These results suggest that celecoxib may affect the pathophysiology of schizophrenia through COX-2-independent actions rather than by inhibiting activity of up-regulated COX-2 protein.

Immunohistochemical examination on intracranial calcification in neurodegenerative diseases

Abstract. Fahr-type calcification is a relatively common finding in the elderly, and in younger patients with Alzheimers disease, calcification in the basal ganglia is not uncommon. However, as far as we know, an immunohistochemical study of intracranial calcification in neurodegenerative diseases has not been performed. In this study, we examined intracranial calcification of the basal ganglia and cerebellum with antibodies against noncollagenous bone matrix proteins. Nineteen brains were employed. The diagnoses were diffuse neurofibrillary tangles with calcification in five, Alzheimers disease in five, Picks disease in one, progressive supranuclear palsy in one, Parkinsons disease in one, and six controls. By conventional histology, three patterns of calcium (Ca) deposition were recognized: diffuse deposition within the tunica media of small and medium-sized vessels (type 1 deposition), free spherical or lobulated concretions (type 2 deposition) in the parenchyma, and rows of small calcospherites lying along capillaries (type 3 deposition). Type 3 deposition is relatively rare, and may be a hallmark of severe intracranial calcification. Immunohistochemistry demonstrated that osteopontin was present diffusely in all Ca deposition types. Osteocalcin was present chiefly in the peripheral region of type 2 and 3 depositions, as well as in only the rims of type 1 deposition. Bone sialoprotein and osteonectin were found only in the core portions of type 2 and 3 depositions. In brief, type 1 deposition shows a different staining pattern from type 2 and 3. Different Ca deposition patterns of noncollagenous bone matrix proteins may suggest their separate roles in the pathogenesis of intracranial calcification.

Increased expression of neuronal cyclooxygenase-2 in the hippocampus in amyotrophic lateral sclerosis both with and without dementia

The pathophysiological basis of cognitive dysfunction, including frontotemporal dementia (FTD), in patients with amyotrophic lateral sclerosis (ALS) and ALS with dementia (ALSD) remains unclear. On the other hand, increased expression of cyclooxygenase-2 (COX-2) in the spinal cord is thought to play a pivotal role in motor neuron degeneration in ALS. In this study, to assess the relationship between the neuronal COX-2 expression in the cerebrum, the formation of tau- and α-synuclein-negative but ubiquitin-positive neuronal inclusions (UPIs), and dementia in motor neuron disease (MND), we examined neuronal COX-2 immunoreactivity in the frontal cortex and hippocampus of patients with non-demented ALS without UPIs (n=11), ALSD with UPIs (n=6), and normal controls (n=24) using a quantitative immunohistochemical technique. Neuronal COX-2 expression in all CA1–4 in the hippocampus was significantly up-regulated in the ALSD group, and, to lesser degree but significantly, in the ALS group. Neuronal COX-2 expression in the frontal cortex was also significantly up-regulated in the ALSD group but not in the ALS group. These findings suggest that (1) the frontal cortex and hippocampus of MND are involved in the same pathogenic process associated with COX-2 induction that has been observed in spinal anterior horn cells, (2) COX-2 induction in the cerebrum is a pathogenic process that can occur even in the absence of UPI formation in MND, and (3) COX-2 expression in the cerebrum may be associated with cognitive dysfunction in MND.

An autopsied case of dementia with Lewy bodies with supranuclear gaze palsy

Abstract A 66-year-old man had suffered from a slow and steady decline in both physical and cognitive function for four years. He showed bradykinesia and small step gait with supranuclear vertical gaze palsy, especially upward gaze palsy. He was started on levodopa therapy but without response. A diagnosis of progressive supranuclear palsy was clinically suspected. He died at age 69. Pathologically, many α-synuclein positive inclusions were detected both in the brain stem and cerebral cortices, and the diagnosis of dementia with Lewy bodies was made. Scattered α-synuclein-positive inclusions and threads, which may be a pathological substrate for supranuclear gaze palsy, were identified in the rostal midbrain. From a review of five cases of dementia with Lewy bodies with supranuclear gaze palsy including this case, the absence of falls in the early stage of the disease, fluctuation of cognition, hallucination and vertical gaze palsy with a more severe defect in the upward direction distinguished dementia with Lewy bodies with vertical gaze palsy from progressive supranuclear palsy. In the differential diagnosis of parkinsonism with gaze palsy, clinicians should consider dementia with Lewy bodies with gaze palsy as well as progressive supranuclear palsy.

Cyclooxygenase-2 in the hippocampus is up-regulated in Alzheimer's disease but not in variant Alzheimer's disease with cotton wool plaques in humans

We examined neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, and neuron densities in the CA1-4 of the hippocampus in three cases of Alzheimers disease with cotton wool plaques (CWP-AD), 17 cases of typical Alzheimers disease without CWPs (tAD), and 26 normal controls. Cyclooxygenase-2 expression was significantly increased in all of the CA1-4 in tAD, but not in any subdivision in CWP-AD, compared with controls. Cyclooxygenase-2 expression in tAD was also significantly up-regulated compared with that in CWP-AD in all subdivisions. Furthermore, neuron density in the hippocampus was not significantly reduced in CWP-AD cases compared with controls despite remarkable intra- and extraneuronal Abeta deposition. These findings suggest that unknown factors besides Abeta deposition are necessary for the cyclooxygenase-2 up-regulation and neurodegeneration in Alzheimers disease.