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Familial AD (familial + ad)
Selected AbstractsA, aggregation and possible implications in Alzheimer's disease pathogenesisJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2009Prashant R. Bharadwaj ,,Introduction ,,Amyloid Structure ,,Mechanism of Amyloid aggregation ,,A,: a natively unfolded protein? ,,Ambiguities in synthetic Ab studies ,,Formation of Amyloid plaques ,,Role of Ab in AD Pathogenesis ,,Conclusion Abstract Amyloid , protein (A,) has been associated with Alzheimer's disease (AD) because it is a major component of the extracellular plaque found in AD brains. Increased A, levels correlate with the cognitive decline observed in AD. Sporadic AD cases are thought to be chiefly associated with lack of A, clearance from the brain, unlike familial AD which shows increased A, production. A, aggregation leading to deposition is an essential event in AD. However, the factors involved in A, aggregation and accumulation in sporadic AD have not been completely characterized. This review summarizes studies that have examined the factors that affect A, aggregation and toxicity. By necessity these are studies that are performed with recombinant-derived or chemically synthesized A,. The studies therefore are not done in animals but in cell culture, which includes neuronal cells, other mammalian cells and, in some cases, non-mammalian cells that also appear susceptible to A, toxicity. An understanding of A, oligomerization may lead to better strategies to prevent AD. [source] Disruption of neurogenesis by amyloid ,-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 6 2002Norman J. Haughey Abstract Neurogenesis occurs in the adult mammalian brain and may play roles in learning and memory processes and recovery from injury, suggesting that abnormalities in neural progenitor cells (NPC) might contribute to the pathogenesis of disorders of learning and memory in humans. The objectives of this study were to determine whether NPC proliferation, survival and neuronal differentiation are impaired in a transgenic mouse model of Alzheimer's disease (AD), and to determine the effects of the pathogenic form of amyloid ,-peptide (A,) on the survival and neuronal differentiation of cultured NPC. The proliferation and survival of NPC in the dentate gyrus of the hippocampus was reduced in mice transgenic for a mutated form of amyloid precursor protein that causes early onset familial AD. A, impaired the proliferation and neuronal differentiation of cultured human and rodent NPC, and promoted apoptosis of neuron-restricted NPC by a mechanism involving dysregulation of cellular calcium homeostasis and the activation of calpains and caspases. Adverse effects of A, on NPC may contribute to the depletion of neurons and cognitive impairment in AD. [source] Pyroglutamate-modified amyloid ,-peptides , A,N3(pE) , strongly affect cultured neuron and astrocyte survivalJOURNAL OF NEUROCHEMISTRY, Issue 6 2002Claudio Russo Abstract N-terminally truncated amyloid-, (A,) peptides are present in early and diffuse plaques of individuals with Alzheimer's disease (AD), are overproduced in early onset familial AD and their amount seems to be directly correlated to the severity and the progression of the disease in AD and Down's syndrome (DS). The pyroglutamate-containing isoforms at position 3 [A,N3(pE),40/42] represent the prominent form among the N-truncated species, and may account for more than 50% of A, accumulated in plaques. In this study, we compared the toxic properties, fibrillogenic capabilities, and in vitro degradation profile of A,1,40, A,1,42, A,N3(pE),40 and A,N3(pE),42. Our data show that fibre morphology of A, peptides is greatly influenced by the C-terminus while toxicity, interaction with cell membranes and degradation are influenced by the N-terminus. A,N3(pE),40 induced significantly more cell loss than the other species both in neuronal and glial cell cultures. Aggregated A,N3(pE) peptides were heavily distributed on plasma membrane and within the cytoplasm of treated cells. A,N3(pE),40/42 peptides showed a significant resistance to degradation by cultured astrocytes, while full-length peptides resulted partially degraded. These findings suggest that formation of N-terminally modified peptides may enhance ,-amyloid aggregation and toxicity, likely worsening the onset and progression of the disease. [source] Prospective Follow-Up of Empirically Derived Alcohol Dependence Subtypes in Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC): Recovery Status, Alcohol Use Disorders and Diagnostic Criteria, Alcohol Consumption Behavior, Health Status, and Treatment SeekingALCOHOLISM, Issue 6 2010Howard B. Moss Background:, We have previously reported on an empirical classification of Alcohol Dependence (AD) individuals into subtypes using nationally representative general population data from the 2001 to 2002 Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and latent class analysis. Our results suggested a typology of 5 separate clusters based upon age of onset of AD, multigenerational familial AD, rates of antisocial personality disorder (ASPD), endorsement of specific AD and Alcohol Abuse (AA) criteria, and the presence of comorbid mood, anxiety, and substance use disorders (SUD). In this report, we focus on the clinical follow-up of these cluster members in Wave 2 of the NESARC (2004 to 2005). Methods:, The mean interval between NESARC Wave 1 and NESARC Wave 2 interviews was 36.6 (SD = 2.6) months. For these analyses, we utilized a Wave 2 NESARC sample that was comprised of a total of 1,172 individuals who were initially ascertained as having past-year AD at NESARC Wave 1 and initially subtyped into one of 5 groupings using latent class analysis. We identified these subtypes as: (i) Young Adult, characterized by very early age of onset, minimal family history, and low rates of psychiatric and SUD comorbidity; (ii) Functional, characterized by older age of onset, higher psychosocial functioning, minimal family history, and low rates of psychiatric and SUD comorbidity; (iii) Intermediate Familial, characterized by older age of onset, significant familial AD, and elevated comorbid rates of mood disorders SUD; (iv) Young Antisocial, characterized by early age of onset and elevated rates of ASPD, significant familial AD, and elevated rates of comorbid mood disorders and SUD; (v) Chronic Severe, characterized by later onset, elevated rates of ASPD, significant familial AD, and elevated rates of comorbid mood disorders and SUD. In this report, we examine Wave 2 recovery status, health status, alcohol consumption behavior, and treatment episodes based upon these subtypes. Results:, Significantly fewer of the Young Adult and Functional subtypes continued to meet full DSM-IV AD criteria in Wave 2 than did the Intermediate Familial, the Young Antisocial, and the Chronic Severe subtypes. However, we did not find that treatment seeking for alcohol problems increased over Wave 1 reports. In Wave 2, Young Antisocial and Chronic Severe subtypes had highest rates of past-year treatment seeking. In terms of health status, the Intermediate Familial, the Young Antisocial, and the Chronic Severe subtypes had significantly worse mental health scores than the Young Adult and Functional subtypes. For physical health status, the Functional, Intermediate Familial, Young Antisocial, and the Chronic Severe subtypes had significantly worse scores than the Young Adult subtype. In terms of alcohol consumption behavior, the Young Adult, Functional, and Young Antisocial subtypes significantly reduced their risk drinking days between Wave 1 and Wave 2, whereas the Intermediate Familial and the Chronic Severe subtypes did not. Discussion:, The results suggest that the empirical AD typology predicts differential clinical outcomes 3 years later. Persistence of full AD, treatment seeking, and worse mental health status were associated most strongly with those subtypes manifesting the greatest degree of psychiatric comorbidity. Reductions in alcohol consumption behavior and good physical health status were seen among the 2 younger subtypes. Overall, the least prevalent subtype, the Chronic Severe, showed the greatest stability in the manifestations of AD, despite having the highest rate of treatment seeking. [source] Heparan Sulfate Accumulation with A, Deposits in Alzheimer's Disease and Tg2576 Mice is Contributed by Glial CellsBRAIN PATHOLOGY, Issue 4 2008Paul O'Callaghan Abstract Amyloid ,-peptide (A,) plaques, one of the major neuropathological lesions in Alzheimer's disease (AD), can be broadly subdivided into two morphological categories: neuritic and diffuse. Heparan sulfate (HS) and HS proteoglycans (HSPGs) are codeposits of multiple amyloidoses, including AD. Although HS has been considered a limiting factor in the initiation of amyloid deposition, the pathological implications of HS in A, deposits of AD remain unclear. In this study, immunohistochemistry combined with fluorescence and confocal microscopy was employed to gain deeper insight into the accumulation of HS with A, plaques in sporadic and familial AD. Here we demonstrate that HS preferentially accumulated around the A,40 dense cores of neuritic plaques, but was largely absent from diffuse A,42 plaques, suggesting that A,42 deposition may occur independently of HS. A codeposition pattern of HS with A, deposits in Tg2576 mice was also examined. We identified the membrane-bound HSPGs, glypican-1 (GPC1) and syndecan-3 (SDC3), in glial cells associated with A, deposits, proximal to sites of HS accumulation. In mouse primary glial cultures, we observed increased levels of GPC1 and SDC3 following A, stimulation. These results suggest that HS codeposits with A,40 in neuritic plaques and is mainly derived from glial cells. [source] | ||||||||||