Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP

JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance, were crossed with Tg2576 transgenic mice expressing mutant beta-amyloid precursor protein (APP), thus modulating the APP-Abeta (beta-amyloid peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Abeta deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Abeta influences the formation of neurofibrillary tangles. The interaction between Abeta and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease.     

Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation

Cerebral cortex samples from patients with Alzheimer's disease and from rats after experimental cholinergic denervation of the cerebral cortex exhibited reductions in the presynaptic marker choline acetyltransferase activity and in the number of M2 muscarine receptors, with no change in the number of M1 receptors. These results are in keeping with evidence that M2 receptors function in cholinergic nerve terminals to regulate the release of acetylcholine, whereas M1 receptors are located on postsynaptic cells and facilitate cellular excitation. New M1-selective agonists and M2-selective antagonists directed at post- or presynaptic sites deserve consideration as potential agents for the treatment of the disease.     

Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease

The deposition of amyloid-beta (Abeta) peptides into amyloid plaques precedes the cognitive dysfunction of Alzheimer's disease (AD) by years. Biomarkers indicative of brain amyloid burden could be useful for identifying individuals at high risk for developing AD. As in AD in humans, baseline plasma Abeta levels in a transgenic mouse model of AD did not correlate with brain amyloid burden. However, after peripheral administration of a monoclonal antibody to Abeta (m266), we observed a rapid increase in plasma Abeta and the magnitude of this increase was highly correlated with amyloid burden in the hippocampus and cortex. This method may be useful for quantifying brain amyloid burden in patients at risk for or those who have been diagnosed with AD.     

铝胁迫对葡萄苗铝吸收分配及抗氧化系统的影响

为了探明葡萄苗在不同浓度铝胁迫下树体的铝积累特征和生理响应,研究以‘水晶’葡萄为试材,在无土栽培条件下,用1.0~8.0 mmol·L~(-1) KAl(SO4)2处理60 d后测定树体铝含量及相关生理指标。结果表明,过量的铝在葡萄苗中的分配为细根粗根老叶树皮嫩叶木质部新枝,2.0 mmol·L~(-1)铝处理后植株生长旺盛,生物量最大,单株铝积累总量最高,5.0 mmol·L~(-1)铝处理后植株生长较弱,生物量较小,单株铝含量最低;铝浓度超过3.0 mmol·L~(-1)时显著降低葡萄苗叶绿素a、叶绿素b、叶绿素a+b的含量,铝浓度超过4.0 mmol·L~(-1)显著降低葡萄苗类胡萝卜素含量;随着铝浓度的增大,葡萄叶片和根系的脯氨酸含量逐渐升高且显著高于CK;铝浓度达到3.0mmol·L~(-1)时,各处理叶片和根系的丙二醛含量均显著高于CK;铝处理提高了葡萄叶片和根系中的氧自由基产生速率和过氧化氢含量;铝胁迫下,葡萄苗叶片和根系的POD活性高于CK;铝浓度低于4.0 mmol·L~(-1)时,SOD活性高于CK,而浓度达到4.0 mmol·L~(-1)时则显著低于CK。可见,低于3.0 mmol·L~(-1)铝对葡萄苗的伤害较小,甚至还能促进其生长,但超过3.0 mmol·L~(-1)铝将对葡萄苗造成不同程度的伤害。     

Plasticity of hippocampal circuitry in Alzheimer's disease

Two markers of neuronal plasticity were used to compare the response of the human central nervous system to neuronal loss resulting from Alzheimer's disease with the response of rats to a similar neuronal loss induced by lesions. In rats that had received lesions of the entorhinal cortex, axon sprouting of commissural and associational fibers into the denervated molecular layer of the dentate gyrus was paralleled by a spread in the distribution of tritiated kainic acid-binding sites. A similar expansion of kainic acid receptor distribution was observed in hippocampal samples obtained postmortem from patients with Alzheimer's disease. An enhancement of acetylcholinesterase activity in the dentate gyrus molecular layer, indicative of septal afferent sprouting, was also observed in those patients with a minimal loss of cholinergic neurons. These results are evidence that the central nervous system is capable of a plastic response in Alzheimer's disease. Adaptive growth responses occur along with the degenerative events.     

Decreased clearance of CNS beta-amyloid in Alzheimer's disease

Alzheimer's disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer's disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer's disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer's disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer's disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer's disease is characterized by an overall impairment in Aβ clearance.     

Biological control of dissolved aluminum in seawater: experimental evidence

Experimental evidence supports the hypothesis that the concentration and distribution of dissolved aluminum in ocean water are controlled by biological activity in the surface waters. The growth of the diatom Skeletonema costatum in artificial seawater media spiked with aluminum reduced the aluminum concentration to that actually found in surface open ocean waters (about 0.5 micrograms per liter). Furthermore, aluminum had a catalytic and limiting effect on the growth of the diatoms.     

不同基因型阿尔茨海默病模型小鼠的脑组织免疫组化研究

用单表达hAPP和hAChE基因的2个转基因小鼠交配,其后代应用PCR方法检测得到4种不同基因型的小鼠。通过脑组织免疫组化分析,进行不同基因型阿尔茨海默病小鼠模型的比较研究。结果显示：野生型和单转hAChE型小鼠在13月龄内的脑组织内嗅皮质及海马均没有β淀粉样沉积、老年斑出现;hAPP转基因小鼠在9月龄时有少量的β淀粉样沉积,出现老年斑;而hAPP／hAChE双表达的转基因型组小鼠在6月龄时就会出现β淀粉样沉积,9月龄和13月龄时则出现明显的老年斑现象。因此,双表达hAPP／hAChE的转基因小鼠是一种理想的用于AD发病机制研究的转基因动物模型。     

脑小血管病与阿尔茨海默病关系研究进展

脑小血管病(CSVD)是一组累及到脑小动脉、微动脉、静脉和毛细血管多病因和病理机制的疾病,主要包含腔隙性脑梗死或腔隙性卒中、脑白质疏松症、Binswanger病和脑微出血.CSVD占全世界卒中的20％,是血管性痴呆和阿尔茨海默病(AD)等认知障碍和痴呆最常见原因.CSVD可促进AD发生,防治脑血管疾病的他汀药物可能对AD有作用.该文着重阐述了AD和CSVD关系,并对AD与腔隙性脑梗死、脑白质疏松症、Binswanger病和脑微出血之间的关系进行了综述,同时分析了CSVD在认知障碍和痴呆发生中的作用.     

Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease

We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-beta peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of beta-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.     

Games played by rogue proteins in prion disorders and Alzheimer's disease

The incidence of Alzheimer's disease (AD) and that of prion disorders (PrD) could not be more different. One-third of octogenarians succumb to AD, whereas Creutzfeldt-Jakob disease typically affects one individual in a million each year. However, these diseases have many common features impinging on the metabolism of neuronal membrane proteins: the amyloid precursor protein APP in the case of AD, and the cellular prion protein PrPC in PrD. APP begets the Abeta peptide, whereas PrPC begets the malignant prion protein PrPSc. Both Abeta and PrPSc are associated with disease, but we do not know what triggers their accumulation and neurotoxicity. A great deal has been learned, however, about protein folding, misfolding, and aggregation; an entirely new class of intramembrane proteases has been identified; and unsuspected roles for the immune system have been uncovered. There is reason to expect that prion research will profit from advances in the understanding of AD, and vice versa.     

Family study of platelet membrane fluidity in Alzheimer's disease

The fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene in labeled platelet membranes, an index of membrane fluidity, identifies a prominent subgroup of patients with Alzheimer's disease who manifest distinct clinical features. In a family study, the prevalence of this platelet membrane abnormality was 3.2 to 11.5 times higher in asymptomatic, first-degree relatives of probands with Alzheimer's disease than in neurologically healthy control subjects chosen without regard to family history of dementia. The pattern of the platelet membrane abnormality within families was consistent with that of a fully penetrant autosomal dominant trait. Thus, this abnormality of platelet membranes may be an inherited factor that is related to the development of Alzheimer's disease.     

Beta amyloid gene duplication in Alzheimer's disease and karyotypically normal Down syndrome

With the recently cloned complementary DNA probe, lambda Am4 for the chromosome 21 gene encoding brain amyloid polypeptide (beta amyloid protein) of Alzheimer's disease, leukocyte DNA from three patients with sporadic Alzheimer's disease and two patients with karyotypically normal Down syndrome was found to contain three copies of this gene. Because a small region of chromosome 21 containing the ets-2 gene is duplicated in patients with Alzheimer's disease, as well as in karyotypically normal Down syndrome, duplication of a subsection of the critical segment of chromosome 21 that is duplicated in Down syndrome may be the genetic defect in Alzheimer's disease.     

ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease

Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. Abeta interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Abeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Abeta interaction and suppresses Abeta-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Abeta-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Abeta interaction may be a therapeutic target in AD.