Journal of Alzheimer's Disease - Volume 22, issue 2

Authors: Timmer, Nienke M. | Kuiperij, H. Bea | de Waal, Robert M.W. | Verbeek, Marcel M.

Article Type: Review Article

Abstract: Senile plaques and cerebral amyloid angiopathy in Alzheimer's disease (AD) patients not only consist of the amyloid-β protein (Aβ), but also contain many different Aβ-associated factors, such as heparan sulfate proteoglycans, apolipoproteins, and complement factors. These factors may all influence Aβ deposition, aggregation, and clearance and therefore seem important in the development of human Aβ deposits. To study AD pathology and test new therapeutic agents, many different mouse models have been created. By transgenic expression of the amyloid-β protein precursor, frequently in combination with other transgenes, these animals develop Aβ deposits that morphologically resemble their human counterparts. Whether this resemblance …also applies to the presence of Aβ-associated factors is largely unclear. In this review, the co-deposition of factors known to associate with human Aβ deposits is summarized for several different AD mouse models. Show more

Keywords: Acute-phase proteins, Alzheimer's disease, amyloid-β, apolipoprotein E, complement, heparan sulfate proteoglycans, transgenic mice

DOI: 10.3233/JAD-2010-100711

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 345-355, 2010

Authors: Mutter, Joachim | Curth, Annika | Naumann, Johannes | Deth, Richard | Walach, Harald

Article Type: Review Article

Abstract: Mercury is one of the most toxic substances known to humans. It has been introduced into the human environment and has also been widely used in medicine. Since circumstantial evidence exists that the pathology of Alzheimer's disease (AD) might be in part caused or exacerbated by inorganic mercury, we conducted a systematic review using a comprehensive search strategy. Studies were screened according to a pre-defined protocol. Two reviewers extracted relevant data independent of each other. One thousand and forty one references were scrutinized, and 106 studies fulfilled the inclusion criteria. Most studies were case control or comparative cohort studies. Thirty-two …studies, out of 40 testing memory in individuals exposed to inorganic mercury, found significant memory deficits. Some autopsy studies found increased mercury levels in brain tissues of AD patients. Measurements of mercury levels in blood, urine, hair, nails, and cerebrospinal fluid were inconsistent. In vitro models showed that inorganic mercury reproduces all pathological changes seen in AD, and in animal models inorganic mercury produced changes that are similar to those seen in AD. Its high affinity for selenium and selenoproteins suggests that inorganic mercurymay promote neurodegenerative disorders via disruption of redox regulation. Inorganic mercury may play a role as a co-factor in the development of AD. It may also increase the pathological influence of other metals. Our mechanistic model describes potential causal pathways. As the single most effective public health primary preventive measure, industrial, and medical usage of mercury should be eliminated as soon as possible. Show more

Keywords: Alzheimer's disease, inorganic mercury, neurotoxicity, selenium, systematic review

DOI: 10.3233/JAD-2010-100705

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 357-374, 2010

Authors: Jiménez, Juan S.

Article Type: Review Article

Abstract: A number of neurodegenerative diseases, including Alzheimer's disease, tauopathies, Parkinson's disease, and synucleinopathies, polyglutamine diseases, including Huntington's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy, are characterized by the existence of a protein or peptide prone to aggregation specific to the disease: amyloid-β, tau protein, α-synuclein, atrophin 1, androgen receptor, prion protein, copper-zinc superoxide dismutase, α 1A subunit of CaV2.1, TATA-box binding protein, huntingtin, and ataxins 1, 2, 3, and 7. Beside this common molecular feature, we have found three additional main properties related to the disease-connected protein or peptide, which are shared by all those neurological disorders: first, proneness …to aggregation, which, in many cases, seems to be bound to the lack of a clearly defined secondary structure; second, reported presence of the disease-related protein inside the nucleus; and finally, an apparently unspecific interaction with DNA. These findings, together with the lack of clear details to explain the molecular origin of these neurodegenerative diseases, invite a hypothesis that, together with other plausible molecular explanations, may contribute to find the molecular basis of these diseases: I propose here the hypothesis that many neurological disorders may be the consequence, at least in part, of an aberrant interaction of the disease-related protein with nucleic acids, therefore affecting the normal DNA expression and giving place to a genetic stress which, in turn, alters the expression of proteins needed for the normal cellular function and regulation. Show more

Keywords: Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, polyglutamine diseases, transmissible spongiform encephalopathy

DOI: 10.3233/JAD-2010-100189

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 375-391, 2010

Authors: Struble, Robert G. | Ala, Tom | Patrylo, Peter R. | Brewer, Gregory J. | Yan, Xiao-Xin

Article Type: Review Article

Abstract: The amyloid cascade hypothesis has guided much of the research into Alzheimer's disease (AD) over the last 25 years. We argue that the hypothesis of amyloid-β (Aβ) as the primary cause of dementia may not be fully correct. Rather, we propose that decline in brain metabolic activity, which is tightly linked to synaptic activity, actually underlies both the cognitive decline in AD and the deposition of Aβ. Aβ may further exacerbate metabolic decline and result in a downward spiral of cognitive function, leading to dementia. This novel interpretation can tie the disparate risk factors for dementia to a unifying hypothesis …and present a roadmap for interventions to decrease the prevalence of dementia in the elderly population. Show more

Keywords: Amyloid-β protein, apolipoprotein E, dementia, etiology, metabolism, mitochondria, pathology, olfactory pathways, therapeutics

DOI: 10.3233/JAD-2010-100846

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 393-399, 2010

Authors: Ross, Joel S. | Imbimbo, Bruno P.

Article Type: Short Communication

Abstract: The recent failure of semagacestat in two large Phase III studies questions the value of γ-secretase inhibitors in treating Alzheimer's disease. Understanding the reasons of this setback may be important for the future research on effective treatments for this devastating disease.

DOI: 10.3233/JAD-2010-101548

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 401-404, 2010

Authors: Gil-Bea, Francisco J. | Solas, Maite | Solomon, Alina | Mugueta, Carmen | Winblad, Bengt | Kivipelto, Miia | Ramirez, Maria J. | Cedazo-Mínguez, Angel

Article Type: Research Article

Abstract: Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly …decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-β 1–42 (Aβ1–42 ) levels and cognitive score. Furthermore, total-tau/(Aβ1–42 *insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aβ1–42 ratio for early AD diagnosis in women. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, insulin, mild cognitive impairment, women

DOI: 10.3233/JAD-2010-100795

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 405-413, 2010

Authors: Rosengarten, Bernhard | Dannhardt, Veren | Burr, Ole | Pöhler, Matthias | Rosengarten, Susanne | Oechsner, Matthias | Reuter, Iris

Article Type: Research Article

Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) lead to a cholinergic deficit in the brain which is not only related to dementia, but may also lead to a disturbed neurovascular coupling. We investigated the effect of cholinergic decline on neurovascular coupling in PD patients. Patients with idiopathic PD were divided in groups without (n = 59; 65 ± 9 y) or with moderate dementia as specified by Mini-Mental State Examination. The demented patients were assigned to groups with (n = 55; 73 ± 6 y) or without (n = 61; 72 ± 8 y) acetylcholinesterase inhibitor treatment. Neurovascular coupling was …assessed by a simultaneous electroencephalography-Doppler technique applying a contrast-based visual stimulation task. Visually evoked potential amplitudes (N75-P100) and parameters of the hemodynamic response in the posterior cerebral artery were obtained using a control system approach (resting flow velocity, gain, attenuation, rate time, and natural frequency). Data were compared to a healthy control group of a similar age range (n = 20; 63 ± 8 yr). Compared to controls, patient groups presented no differences in evoked potential amplitudes or neurovascular coupling parameters. The reported 30% decline in acetylcholinesterase activity in PD patients did not lead to measurable changes in neurovascular coupling. In AD patients additional factors might explain the uncoupling and higher cerebrovascular risk detected in clinical studies. Show more

Keywords: Alzheimer's disease, cerebral blood flow, dementia, functional activation, neurovascular coupling, Parkinson's disease, visually evoked potential

DOI: 10.3233/JAD-2010-101140

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 415-421, 2010

Authors: Kapoor, Arun | Hsu, Wen-Ming | Wang, Bo-Jeng | Wu, Guan-Hsun | Lin, Ti-Yu | Lee, Shyh-Jye | Yen, Chen-Tung | Liang, Shu-Mei | Liao, Yung-Feng

Article Type: Research Article

Abstract: Amyloidogenic processing of amyloid-β precursor protein (AβPP) is associated with cholesterol- and sphingolipid-rich lipid rafts. Caveolin-1, a raft-residing protein, has been implicated in the pathogenesis of Alzheimer's disease. To determine the role of caveolin-1 in governing γ-secretase-mediated AβPP proteolysis, cellular γ-secretase activity was assessed in response to alteration in caveolin-1 expression. We demonstrated that suppression of caveolin-1 expression by RNA interference resulted in a significant increase in γ-secretase-mediated proteolysis of AβPP, generation of amyloid-β, and cleavage of Notch. Overexpression of caveolin-1 attenuated γ-secretase-mediated proteolysis of AβPP and Notch, substantiating the negative regulation of γ-secretase by caveolin-1. Furthermore, we found that …cells deficient in caveolin-1 exhibited significantly increased co-localization of γ-secretase with clathrin-coated non-caveolar endocytic vesicles, demonstrating that the partitioning of γ-secretase between caveolar and non-caveolar membranes can be modulated by caveolin-1. Our data also showed that JNK activation is essential for caveolin-1-mediated regulation of γ-secretase. Together, our results strongly suggest that caveolin-1 is an important regulator of γ-secretase activity. Show more

Keywords: Amyloid-β, amyloid-β precursor protein, caveolin-1, clathrin, γ-secretase, lipid raft

DOI: 10.3233/JAD-2010-100531

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 423-442, 2010

Authors: Liu, Dong | Pitta, Michael | Lee, Jong-Hwan | Ray, Balmiki | Lahiri, Debomoy K. | Furukawa, Katsutoshi | Mughal, Mohamed | Jiang, Haiyang | Villarreal, Julissa | Cutler, Roy G. | Greig, Nigel H. | Mattson, Mark P.

Article Type: Research Article

Abstract: Compromised cellular energy metabolism, cerebral hypoperfusion, and neuronal calcium dysregulation are involved in the pathological process of Alzheimer's disease (AD). ATP-sensitive potassium (KATP ) channels in plasma membrane and inner mitochondrial membrane play important roles in modulating neuronal excitability, cell survival, and cerebral vascular tone. To investigate the therapeutic potential of drugs that activate KATP channels in AD, we first characterized the effects of the KATP channel opener diazoxide on cultured neurons, and then determined its ability to modify the disease process in the 3xTgAD mouse model of AD. Plasma and mitochondrial membrane potentials, cell excitability, intracellular Ca2+ …levels and bioenergetics were measured in cultured cerebral cortical neurons exposed to diazoxide. Diazoxide hyperpolarized neurons, reduced the frequency of action potentials, attenuated Ca2+ influx through NMDA receptor channels, and reduced oxidative stress. 3xTgAD mice treated with diazoxide for 8 months exhibited improved performance in a learning and memory test, reduced levels of anxiety, decreased accumulation of Aβ oligomers and hyperphosphorylated tau in the cortex and hippocampus, and increased cerebral blood flow. Our findings show that diazoxide can ameliorate molecular, cytopathological, and behavioral alterations in a mouse model of AD suggesting a therapeutic potential for drugs that activate KATP channels in the treatment of AD. Show more

Keywords: 3xTgAD, calcium, cerebral blood flow, diazoxide, excitotoxicity, hippocampus, hyperpolerization, learning and memory, K ATP channels

DOI: 10.3233/JAD-2010-101017

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 443-457, 2010

Authors: Popp, Julius | Lewczuk, Piotr | Frommann, Ingo | Kölsch, Heike | Kornhuber, Johannes | Maier, Wolfgang | Jessen, Frank

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-β1–42 (Aβ1–42 ) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of Aβ1–42 and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOEε4 allele, on the CSF Aβ1–42 and pTau181 concentrations in 280 adults …with normal cognition across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF Aβ1–42 and pTau181, and of the APOEε4 genotype on the Aβ1–42 levels in the cognitively normal participants. Carrying the APOEε4 allele was associated with a significant decrease of the Aβ1–42 concentrations in middle-aged and older participants. In the group of participants with AD, the Aβ1–42 levels were significantly lower in the APOEε4 carriers compared to the non-carriers. These findings demonstrate significant age effects on the CSF Aβ1–42 and pTau181 across lifespan. They also suggest that the decrease of Aβ1–42 , but not the increase of pTau181 CSF levels is accelerated by the APOEε4 genotype in middle-aged and older adults with normal cognition. Show more

Keywords: Alzheimer's disease, amyloid-β, APOEε4, cerebrospinal fluid, hyperphosphorylated tau, normal aging

DOI: 10.3233/JAD-2010-100561

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 459-468, 2010