Ferric cycle activity and Alzheimer disease

Elevated plasma homocysteine is an independent risk factor for the development of Alzheimer disease, however, the precise mechanisms underlying this are unclear. In this article, we expound on a novel hypothesis depicting the involvement of homocysteine in a vicious circle involving iron dysregulation and oxidative stress designated as the ferric cycle (Dwyer et al., 2004). Moreover, we suspect that the development of a critical heme deficiency in vulnerable neurons is an additional consequence of ferric cycle activity. Oxidative stress and heme deficiency are consistent with many pathological changes found in Alzheimer disease including mitochondrial abnormalities and impaired energy metabolism, cell cycle and cell signaling abnormalities, neuritic pathology, and other features of the disease involving alterations in iron homeostasis such as the abnormal expression of heme oxygenase-1 and iron response protein 2. Based on the ferric cycle concept, we have developed a model of Alzheimer disease development and progression, which offers an explanation for why sporadic Alzheimer disease is different than normal aging and why familial Alzheimer disease and sporadic Alzheimer disease could have different etiologies but a common end-stage.     

Altered cell-matrix associated ADAM proteins in Alzheimer disease

Alterations in cell-matrix 'contact' are often related to a disruption of cell cycle regulation and, as such, occur variously in neoplasia. Given the recent findings showing cell cycle alterations in Alzheimer disease, we undertook a study of ADAM-1 and 2 (A Disintegrin And Metalloprotease), developmentally-regulated, integrin-binding, membrane-bound metalloproteases. Our results show that whereas ADAM-1 and 2 are found in susceptible hippocampal neurons in Alzheimer disease, these proteins were not generally increased in similar neuronal populations in younger or age-matched controls except in association with age-related neurofibrillary alterations. This increase in both ADAM-1 and 2 in cases of Alzheimer disease was verified by immunoblot analysis (P < 0.05). An ADAM-induced loss of matrix integration would effectively "reset" the mitotic clock and thereby stimulate re-entry into the cell cycle in neurons in Alzheimer disease. Furthermore, given the importance of integrins in maintaining short-term memory, alterations in ADAM proteins or their proteolytic activity could also play a proximal role in the clinico-pathological manifestations of Alzheimer disease.     

Altered cellular distribution of iron in rat cerebral cortex during the oestrous cycle

Summary. Iron levels in blood, liver and the substantia nigra fluctuate during the oestrous cycle but it is not known whether the cellular distribution also changes. This study shows that during dioestrus, when serum levels of oestradiol are low, the amount of histochemically detectable iron in the cerebral cortex is significantly lower than in proestrus when oestradiol levels are highest. During dioestrus iron is concentrated within neurones, and the transition to proestrus is associated with a shift in iron localisation from neurones to vascular endothelial cells and oligodendrocytes. These data raise the possibility that changes in the concentration of serum oestrogen (or other reproductive hormones) during the oestrous cycle can influence the intercellular transport of iron in the brain.Current address: Neuroplasticity Department, European Neuroscience Institute, Göttingen, Germany     

Cyclin' toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease

Recent evidence has associated the aberrant, proximal re-expression of various cell cycle control elements with neuronal vulnerability in Alzheimer disease, a chronic neurodegeneration. Such ectopic localization of various cyclins, cyclin-dependent kinases, and cyclin inhibitors in neurons can be seen as an attempt to re-enter the cell cycle. Given that primary neurons are terminally differentiated, any attempted re-entry into the cell division cycle in this postmitotic environment will be dysregulated. Since successful dysregulation of the cell cycle is also the hallmark of a neoplasm, early cell-cycle pathophysiology in Alzheimer disease may recruit oncogenic signal transduction mechanisms and, hence, can be viewed as an abortive neoplastic transformation.     

Altered lymphocyte distribution in Alzheimer's disease

The contribution of immunological factors in the etiopathogenesis of Alzheimer's disease (AD) is increasingly noted. Apart from cerebral immunological findings, peripheral changes of the immune systems have been reported including lymphocyte function and subset distribution. As data still remain inconsistent, we investigated a sample of 43 patients with AD and of 34 healthy age-matched controls. Distribution of the T-, B- and NK cell subsets was determined by flow cytometry (FACS). We found a significant decrease of CD3(+) lymphocytes as well as of CD19(+) lymphocytes. A slight increase of the CD4(+) and a decrease of the CD8(+) subpopulation could be observed, without significant change of the CD4(+)/CD8(+) ratio. CD16(+)56(+) cells were not altered. Our findings of decreased T- and B-Cell numbers in AD sustain the hypothesis of a general decline of immune activity in AD. A putative association with premature immunosenescence in AD and possible pathogenetic implications are discussed.     

Targeting transcriptional regulators to regenerate midbrain dopaminergic axons in Parkinson's disease

<正>Introduction:Parkinson’s disease(PD)is a chronic,age-related neurodegenerative disorder that affects 1–2%of the population over the age of 65.PD is characterised by the progressive degeneration of nigrostriatal dopaminergic(DA)neurons.This leads to disabling motor symptoms,due to the striatal DA denervation.Despite decades of research,     

Altered apolipoprotein D expression in the brain of patients with Alzheimer disease

The etiology of late-onset Alzheimer disease is poorly understood. Predisposing factors such as the apolipoprotein E4 allele, as well as protective factors (e.g., antioxidants) have been proposed to play a role in the disease's process. A search for predisposing factors contributing to sporadic late-onset Alzheimer disease was initiated using the differential display technique. RNA expression profiles of the entorhinal cortex and the cerebellum of Alzheimer-diseased and normal patients were compared. The entorhinal cortex is the first brain region to accumulate neurofibrillary tangles during disease progression, whereas the cerebellum is spared. In the Alzheimer cases of this study, one signal showing preferential expression in the entorhinal cortex corresponded to the apolipoprotein D gene. This preferential expression might be genuine at the RNA level as suggested by the in situ hybridization method used. In addition, immunohistochemical experiments showed higher percentages of Apolipoprotein D reactive pyramidal neurons in the entorhinal cortex and region 1 of Ammon's horn in diseased patients. This increase correlated with the number of neurofibrillary tangles in Alzheimer as well as in normal patients. Colocalization of Apolipoprotein D proteins and neurofibrillary tangles in the same neuron was rare. Thus, these results suggest that in Alzheimer disease and aging, apolipoprotein D gene expression is increased in stressed cortical neurons before they possibly accumulate neurofibrillary tangles.     

阿尔茨海默病细胞移植方式研究进展

阿尔茨海默病是一种神经退行性病变,主要表现为记忆力下降和认知功能受损。传统的 药物治疗效果欠佳,细胞治疗是治疗阿尔茨海默病的新途径。目前针对阿尔茨海默病研究多侧重于工 具细胞治疗阿尔茨海默病机制和工具细胞筛选。现主要对针对工具细胞移植方式进行总结综述     

Cell cycle markers in the hippocampus in Alzheimer’s disease

Using immunohistochemistry we have analysed the nuclear expression of cyclins A, B, D, and E in neurones in the hippocampi of control subjects and patients suffering from various neurodegenerative disorders including Alzheimer’s disease (AD). Cyclins A and D could not be detected but varying degrees of cyclin E expression were found in all patient groups including control subjects. Cyclin B expression was not detected in control subjects but it was expressed in the subiculum, dentate gyrus and CA1 region in patients with AD-type pathology and in the CA2 region and the dentate gyrus of cases of Pick’s disease. These reults suggest that some neurones may have re-entered the cell cycle. The expression of cyclin E without cyclin A expression may indicate an arrest in G₁ with the possibility of re-differentiation and exit from G₁ to G₀. The expression pattern of cyclin E indicates that re-entry into the cell cycle is possible even in control patients, but it is accentuated in patients with AD-related pathology. However, cyclin B was only expressed in AD patients and occurred in areas that were severely affected by pathology. Neurones with cyclin B-reactive nuclei in AD were AT8 positive but did not contain fully developed tangles. In neurones, where cyclin B is expressed, it would appear that the G₁/S checkpoint has been bypassed and that the cell cycle is arrested in G₂. It is proposed that these neurones do not have the opportunity for subsequent re-differentiation. Since factors known to be present in G₂ seem to be responsible for microtubule destabilisation and hyperphosphorylation of tau we hypothesise that cell cycle disturbances may be important in the pathogenesis of AD. Received: 26 September 1996 / Revised, accepted: 20 November 1996     

Regional distribution of alpha-synuclein pathology in unimpaired aging and Alzheimer disease

The amygdaloid complex (AC) was found highly vulnerable to alpha-synuclein (alphaS) pathology in both familial and sporadic Alzheimer disease (AD), and recently, incidental Lewy bodies (LBs) were identified primarily in the lower brainstem. This challenges the traditional view that the substantia nigra (SN) is the region that is predominately affected in the spectrum of LB disorders. We examined the immunoreactivity of alphaS in the SN, the nucleus basalis of Meynert (nbM), and the AC in 904 subjects with or without concomitant AD pathology. AlphaS-positive structures were seen in at least one of the studied brain areas in 121 subjects (13%). The affected regions in the alphaS-positive subjects included the SN (89%), the nbM (73%), and the AC (67%). This study also included 82 sporadic AD patients diagnosed using CERAD criteria. AlphaS-positive structures were seen in 32% of the AD patients, with the SN and AC being equally affected. In a few subjects the AC was the only affected area. However, this was not inevitably associated with AD pathology, but was related to cognitive decline. Incidental LBs in the SN were described in the occasional subjects, with no alphaS pathology in the lower brainstem.     

Stable size distribution of amyloid plaques over the course of Alzheimer disease

Amyloid β plaques are a key pathologic feature of Alzheimer disease (AD), but whether plaque sizes increase or stabilize over the course of AD is unknown. We measured the size distribution of total immunoreactive (10D5-positive) and dense-core (Thioflavin S-positive) plaques in the temporal neocortex of a large group of subjects with AD and age-matched plaque-bearing subjects without dementia to test the hypothesis that amyloid plaques continue to grow along with the progression of the disease. The size of amyloid β (10D5)-positive plaques did not differ between groups, whereas dense-core plaques from the group with AD were slightly larger than those from the group without dementia (～25%-30%, p = 0.01). Within the group with AD, dense-core plaque size did not independently correlate with duration of clinical disease (from 4 to 21 years, p = 0.68), whereas 10D5-positive plaque size correlated negatively with disease duration (p = 0.01). By contrast, an earlier age of symptom onset strongly predicted a larger postmortem plaque size; this effect was independent of disease duration and the presence of the APOE[Latin Small Letter Open E]4 allele (p = 0.0001). We conclude that plaques vary in size among patients, with larger size distributions correlating with an earlier age of onset, but plaques do not substantially increase in size over the clinical course of the disease.