Alzheimer Disease: Zhong Z

Ewers M, Zhong Z, Bürger K, Wallin A, Blennow K, Teipel SJ, Shen Y, Hampel H. · Department of Psychiatry, Alzheimer Memorial Center, Ludwig-Maximilian University, Munich, Germany. · Brain. · Pubmed #18334538 links to  free full text

Abstract: The Apolipoprotein (ApoE) epsilon 4 allele is a major genetic risk factor of Alzheimer's disease, and may affect the production of amyloid beta (A beta(1-42)). Recently, we have shown that beta-secretase (BACE 1) activity can be reliably detected within the brain and human CSF. Here, we have examined an association between the ApoE genotype and CSF-levels of BACE 1 activity in Alzheimer's disease and mild cognitive impairment (MCI). A total of 148 subjects were included: 60 Alzheimer's disease patients, 51 MCI subjects and 37 elderly healthy controls. The CSF-levels of A beta(1-42), BACE 1 activity and BACE protein were measured in all of these subjects. The differences between ApoE-epsilon 4 carriers and ApoE-epsilon 4 non-carriers in these CSF-based measures were determined controlling for gender, age and MMSE score. The ApoE-epsilon 4 genotype was associated with increased BACE 1 activity in both Alzheimer's disease (P = 0.03) and MCI (P = 0.04) subjects. Levels of A beta(1-42) were decreased in ApoE-epsilon 4 carriers in MCI (P = 0.004) but not Alzheimer's disease subjects. This study is the first to demonstrate the association between ApoE-epsilon 4 and CSF-BACE 1 activity in MCI and Alzheimer's disease subjects. The assessment of BACE 1 in CSF may provide a sensitive measure to detect in vivo alterations in the amyloidogenic processing potentially modified by the ApoE genotype.

Yu H, Li WM, Kan KK, Ho JM, Carlier PR, Pang YP, Gu ZM, Zhong Z, Chan K, Wang YT, Han YF. · Institute of Chinese Medical Sciences, University of Macau, Macau SAR, PR China. · J Pharm Biomed Anal. · Pubmed #17931815 No free full text.

Abstract: The lipophilicity and solubility profiles of bis(12)-hupyridone (B12H) and bis(7)-tacrine (B7T), two novel acetylcholinesterase inhibitors dimerized from huperzine A fragments and tacrine, respectively, were investigated over a broad pH range. Lipophilicity was assessed by both shake flask method with 1-octanol-water system and a reverse-phase HPLC system with methanol-water as mobile phase. The former method was used for determining the lipophilicities of the ionized forms (log D) of the dimers while the latter method was used for that of the neutral forms (log P). The log P values for B12H and B7T were found to be 5.4 and 8.2, respectively, indicating that the two dimers are highly lipophilic. The solubilities of both dimers were found to be affected by pH. The solubility of B12H was >1.41 mg/ml when the pH was <7, but <0.06 mg/ml when the pH was >8. The solubility of B7T was >0.26 mg/ml when the pH was <9, but <0.005 mg/ml when the pH was >12. The ionic strength of a solution could affect the solubilities considerably (11.16 mg/ml for B12H and 12.71 mg/ml for B7T in water; 2.07 mg/ml for B12H and 0.36 mg/ml for B7T in saline). The ionization constants (pK(a)) of the two dimers were determined by UV spectrophotometry. Both dimers were found to have two pK(a) values: 7.5+/-0.1 (pK(a1)) and 10.0+/-0.2 (pK(a2)) for B12H; and 8.7+/-0.1 (pK(a1)) and 10.7+/-0.4 (pK(a2)) for B7T. Furthermore, an in vivo pharmacological assay conducted in mice showed that a maximum AChE inhibition occurred 15 min after the single-dose and intraperitoneal administration of either dimer. This indicates that the two dimers may easily cross the blood-brain barrier. In summary, these physiochemical characteristics suggest that the two dimers may be promising candidates for the development of better drugs for Alzheimer's disease.

He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, Staufenbiel M, Li R, Shen Y. · Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351, USA. · J Cell Biol. · Pubmed #17724122 links to  free full text

Abstract: The tumor necrosis factor type 1 death receptor (TNFR1) contributes to apoptosis. TNFR1, a subgroup of the TNFR superfamily, contains a cytoplasmic death domain. We recently demonstrated that the TNFR1 cascade is required for amyloid beta protein (Abeta)-induced neuronal death. However, the function of TNFR1 in Abeta plaque pathology and amyloid precursor protein (APP) processing in Alzheimer's disease (AD) remains unclear. We report that the deletion of the TNFR1 gene in APP23 transgenic mice (APP23/TNFR1(-/-)) inhibits Abeta generation and diminishes Abeta plaque formation in the brain. Genetic deletion of TNFR1 leads to reduced beta-secretase 1 (BACE1) levels and activity. TNFR1 regulates BACE1 promoter activity via the nuclear factor-kappaB pathway, and the deletion of TNFR1 in APP23 transgenic mice prevents learning and memory deficits. These findings suggest that TNFR1 not only contributes to neurodegeneration but also that it is involved in APP processing and Abeta plaque formation. Thus, TNFR1 is a novel therapeutic target for AD.

Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, Marky A, Lenting PJ, Wu Z, Zarcone T, Goate A, Mayo K, Perlmutter D, Coma M, Zhong Z, Zlokovic BV. · Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research, Department of Neurosurgery, University of Rochester Medical School, Rochester, New York 14642, USA. · Nat Med. · Pubmed #17694066 No free full text.

Abstract: Low-density lipoprotein receptor-related protein-1 (LRP) on brain capillaries clears amyloid beta-peptide (Abeta) from brain. Here, we show that soluble circulating LRP (sLRP) provides key endogenous peripheral 'sink' activity for Abeta in humans. Recombinant LRP cluster IV (LRP-IV) bound Abeta in plasma in mice and Alzheimer's disease-affected humans with compromised sLRP-mediated Abeta binding, and reduced Abeta-related pathology and dysfunction in a mouse model of Alzheimer disease, suggesting that LRP-IV can effectively replace native sLRP and clear Abeta.

Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, Hiltunen M, Yang SH, Zhong Z, Shen Y, Simpkins JW, Tanzi RE. · Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA. · Neuron. · Pubmed #17553422 links to  free full text

Abstract: Beta-site APP-cleaving enzyme (BACE) is required for production of the Alzheimer's disease (AD)-associated Abeta protein. BACE levels are elevated in AD brain, and increasing evidence reveals BACE as a stress-related protease that is upregulated following cerebral ischemia. However, the molecular mechanism responsible is unknown. We show that increases in BACE and beta-secretase activity are due to posttranslational stabilization following caspase activation. We also found that during cerebral ischemia, levels of GGA3, an adaptor protein involved in BACE trafficking, are reduced, while BACE levels are increased. RNAi silencing of GGA3 also elevated levels of BACE and Abeta. Finally, in AD brain samples, GGA3 protein levels were significantly decreased and inversely correlated with increased levels of BACE. In summary, we have elucidated a GGA3-dependent mechanism regulating BACE levels and beta-secretase activity. This mechanism may explain increased cerebral levels of BACE and Abeta following cerebral ischemia and existing in AD.

Zhong Z, Ewers M, Teipel S, Bürger K, Wallin A, Blennow K, He P, McAllister C, Hampel H, Shen Y. · Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351, USA. · Arch Gen Psychiatry. · Pubmed #17548753 links to  free full text

Abstract: CONTEXT: Elevated beta-secretase (beta-site amyloid precursor protein-cleaving enzyme 1 [BACE1]) activity has been found in the brains of patients with sporadic Alzheimer disease (AD) compared with controls. Now we are particularly interested in whether BACE1 can be identified in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI), a population at high risk for AD. The possible presence of BACE1 in the CSF of patients with AD and MCI has so far gone unreported. OBJECTIVE: To examine whether BACE1 can be identified in the CSF of patients with MCI. DESIGN: We evaluated CSF BACE1 levels using 2 sandwich enzyme-linked immunosorbent assays, BACE1 enzymatic activities by means of synthetic fluorescence substrate, and total amyloid-beta peptide levels using a sandwich enzyme-linked immunosorbent assay. SETTING: Two independent research centers. PARTICIPANTS: Eighty patients with sporadic AD, 59 patients with MCI, and 69 controls. MAIN OUTCOME MEASURES: BACE1 levels and enzymatic activities and amyloid-beta peptide levels. RESULTS: Increased CSF levels of BACE1 protein were associated with increased risk ratios (RRs) for patients with MCI compared with controls (RR, 2.08; 95% confidence interval [CI], 1.58-2.58) and patients with AD (RR, 1.65; 95% CI, 1.19-2.03). Similarly, patients with MCI showed increased levels of BACE1 activity compared with controls (RR, 2.17; 95% CI, 1.66-2.71) and patients with AD (RR, 3.71; 95% CI, 2.74-4.36). For total amyloid-beta peptide and tau, increased CSF levels were associated with a higher risk of MCI compared with controls. The BACE1 activity was significantly correlated with BACE1 protein level (rho = 0.23; P<.001) and amyloid-beta peptide level (rho = 0.39; P<.001), with amyloid-beta peptide correlated with BACE1 protein level (rho = 0.30; P<.001). CONCLUSION: Significant elevation of BACE1 levels and activity in CSF is an indicator of MCI, which could be an early stage of AD.

Shen Y, He P, Zhong Z, McAllister C, Lindholm K. · Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute 3501, West Santa Fe Drive, Sun City, AZ 85351, USA. · Trends Mol Med. · Pubmed #17055782 No free full text.

Abstract: Abundant neuron loss is a major feature of Alzheimer's disease (AD). Hypotheses for this loss include abnormal amyloid precursor protein processing (i.e. excess Abeta production, protein aggregation or misfolding), oxidative stress, excitotoxicity and inflammation. Neuron loss is a major cause of dementia in AD; however, it seems that there is no definitive pathway that causes cell death in the AD brain. Here, we examine the hypotheses for neuron loss in AD and pose the argument that the means by which neurons degenerate is irrelevant for cognitive decline. The best treatment for cognitive decline is to prevent the toxicity that first sets the neuron on its path to destruction, which is the production of Abeta peptide.

Zhong Z, Qu Z, Wang N, Wang J, Xie Z, Zhang F, Zhang W, Lu Z. · Guangxi College of TCM, Nanning 530001. · Zhong Yao Cai. · Pubmed #15981887 No free full text.

Abstract: OBJECTIVE: To observe the protective effect of Panax notoginseng saponins (PNS) against pathological lesion of cholinergic neuron in rat model with Alzheimer' s disease (AD). METHODS: The AD rat model was established by intra-peritoneal injection of D-galactose combined with excitatory neurotoxin ibotenic acid (IBA) injection into bilateral nbM. The activity and content of choline acetyltransferase (ChAT), the cell morphology and number of cholinergic neuron in brain were determined by immunohistochemistry analysis. RESULTS: PNS could reduce the pathological lesion of cholinergic neuron, including the level of ChAT and number of cholinergic neuron, as compared with those of model group's rats. CONCLUSION: PNS plays a protective role in pathological lesion of cholinergic neuron in AD rat model.