Alzheimer Disease: Troncoso JC

Oh ES, Troncoso JC, Fangmark Tucker SM. · Department of Medicine, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Ave., Baltimore, MD 21205, USA. · Neuromolecular Med. · Pubmed #18543125 links to  free full text

Abstract: Amyloid plaques are composed primarily of amyloid-beta (Abeta) peptides derived from proteolytic cleavage of amyloid precursor protein (APP) and are considered to play a pivotal role in Alzheimer's disease (AD) pathogenesis. Presently, AD is diagnosed after the onset of clinical manifestations. With the arrival of novel therapeutic agents for treatment of AD, there is an urgent need for biomarkers to detect early stages of AD. Measurement of plasma Abeta has been suggested as an inexpensive and non-invasive tool to diagnose AD and to monitor Abeta modifying therapies. However, the majority of cross-sectional studies on plasma Abeta levels in humans have not shown differences between individuals with AD compared to controls. Similarly, cross-sectional studies of mouse plasma Abeta have yielded inconsistent trends in different mouse models. However, longitudinal studies appear to be more promising in humans. Recently, efforts to modify plasma Abeta levels using modulators have shown some promise. In this review, we will summarize the present data on plasma Abeta in humans and mouse models of AD. We will discuss the potential of modulators of Abeta levels in plasma, including antibodies and insulin, and the challenges associated with measuring plasma Abeta. Modulators of plasma Abeta may provide an important tool to optimize plasma Abeta levels and may improve the diagnostic potential of this approach.

Iacono D, O'Brien R, Resnick SM, Zonderman AB, Pletnikova O, Rudow G, An Y, West MJ, Crain B, Troncoso JC. · Division of Neuropathology, Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA. · J Neuropathol Exp Neurol. · Pubmed #18520776 links to  free full text

Abstract: The pathologic changes of Alzheimer disease (AD) evolve very gradually over decades before the disease becomes clinically manifest. Thus, it is not uncommon to find substantial numbers of Abeta plaques and neurofibrillary tangles in autopsy brains of older subjects with documented normal cognition, a state that we define as asymptomatic AD (ASYMAD). The goal of this study is to understand the morphometric substrate of ASYMAD subjects compared with mild cognitive impairment and definite AD cases. We used designed-based stereology to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in 4 cerebral regions: anterior cingulate gyrus, posterior cingulate gyrus, primary visual cortex, and CA1 of hippocampus. We examined and compared autopsy brains from 4 groups (n = 15 each) of participants in the Baltimore Longitudinal Study of Aging: ASYMAD, mild cognitive impairment, AD, and age-matched controls. We found significant hypertrophy of the neuronal cell bodies, nuclei, and nucleoli of CA1 of hippocampus and anterior cingulate gyrus neurons in ASYMAD subjects compared with control and mild cognitive impairment cases. In the posterior cingulate gyrus and primary visual cortex, the hypertrophy was limited to the nuclei and nucleoli. The hypertrophy of cortical neurons and their nuclei and nucleoli in ASYMAD may represent an early reaction to the presence of neurotoxic Abeta or tau, or a compensatory mechanism that prevents the progression of the disease into dementia.

Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O'Brien RJ. · Department of Pathology, Johns Hopkins University, Baltimore, MD, USA. · Ann Neurol. · Pubmed #18496870 links to  free full text

Abstract: OBJECTIVE: To define the magnitude and mechanism of the effect of brain infarcts on the odds of dementia in a prospective study. METHODS: We examined the effects of brain infarcts and Alzheimer's disease (AD) pathology on the risk for dementia in 179 subjects from the Baltimore Longitudinal Study of Aging Autopsy Program. All subjects had longitudinal clinical and cognitive evaluations, and underwent postmortem examination of the brain. RESULTS: Brain infarcts were common in our cohort, and both symptomatic and asymptomatic infarcts conferred a significant increase in the odds of dementia. Risk factors for stroke in the absence of an infarct did not increase the odds of dementia, which was quantitatively related to the number but not the size of hemispheral infarcts; deep subcortical infarcts conferred no increased risk for dementia. The contribution of microscopic infarcts to dementia was significant and equivalent to that of macroscopic infarcts. In subjects with intermediate AD pathology scores, a single macroscopic hemispheral infarct was sufficient to cause dementia. A logistic regression model of the effect of infarcts and AD pathology on dementia indicated that AD pathology alone accounts for 50% of the dementia seen in this cohort, and that hemispheral infarcts alone or in conjunction with AD pathology account for 35%. INTERPRETATION: Cerebrovascular disease is a significant and potentially preventable cause of dementia in the Baltimore Longitudinal Study of Aging. Burden and location of infarcts are significantly associated with cognitive decline.

Tucker SM, Borchelt DR, Troncoso JC. · Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. · J Neuropathol Exp Neurol. · Pubmed #18091561 No free full text.

Abstract: Recent studies have demonstrated the potential utility of antibodies for the treatment of Alzheimer disease (AD). In transgenic mouse models of AD, peripheral and intracerebral administration of Abeta-specific antibodies reduces amyloid burdens to varied extents. The mechanism may involve clearance of pre-existing amyloid plaques or prevention of new amyloid formation. Here, we have used two transgenic models, the inducible CamKII-ttAxtetAPP/swe/ind (Line 107) and the APPswe/PS1dE9 (Line 85), to test the ability of intracerebral injection of Abeta antibodies to clear amyloid. Because the production of Abeta peptides in the Line 107 model is inducible, whereas production in Line 85 mice is constitutive, we could study the effects of antibody on pre-existing plaques versus continuous plaque formation. In Line 85, injection of antibody resulted in modest but statistically significant reductions in amyloid burden (average, 14%-16%). However, injected antibodies had no effect on amyloid burden in Line 107 under conditions in which the production of Abeta was suppressed, indicating that pre-existing plaques are not rapidly cleared. These results indicate that intracerebral injection of Abeta antibodies produces modest reductions in amyloid deposition in these two models and that the mechanism may involve prevention of amyloid formation rather than clearance of pre-existing plaques.

Morgan MD, Mielke MM, O'Brien R, Troncoso JC, Zonderman AB, Lyketsos CG. · Johns Hopkins University, Baltimore, MD 21224, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17804951 links to  free full text

Abstract: The prevalence of major depression is increased in Alzheimer disease (AD), but currently the basis of this association remains unclear. The present study examined rates of depression in 4 groups of participants with postmortem examination from the Baltimore Longitudinal Study of Aging: (1) cognitively normal controls with no Alzheimer pathology, (2) cognitively normal individuals with Alzheimer pathology, (3) individuals with mild cognitive impairment plus Alzheimer pathology, (4) individuals with clinical diagnoses of dementia plus Alzheimer pathology. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Individuals with Alzheimer pathology but no cognitive decline before death had significantly lower rates of depression than cognitively normal controls with no Alzheimer pathology and individuals with Alzheimer pathology plus clinical diagnoses of dementia. These findings suggest that depression is a risk factor for AD in the presence of AD pathology, but depression is not a risk factor for AD pathology.

Riudavets MA, Iacono D, Resnick SM, O'Brien R, Zonderman AB, Martin LJ, Rudow G, Pletnikova O, Troncoso JC. · Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neurobiol Aging. · Pubmed #17599696 links to  free full text

Abstract: This study focuses on the morphometric changes of neurons in asymptomatic Alzheimer's disease (AD), a state characterized by the presence of AD lesions in subjects without cognitive impairment. In autopsy brains, we used stereological methods to compare the cell body and nuclear volumes of anterior cingulate gyrus (ACG) and CA1 hippocampal neurons in asymptomatic AD subjects (n=9), subjects with AD dementia (AD, n=8), mild cognitive impairment (MCI, n=9), and age-matched controls (controls, n=9). In ACG, we observed a significant decrease in the neuronal volume of MCI and AD compared to controls; by contrast, no atrophy was present in asymptomatic AD. Moreover, we found a significant increase in nuclear volume in asymptomatic AD compared to controls (P<0.001), MCI (P<0.01) and AD (P<0.001) brains. Similar results were found in the CA1 region of the hippocampus. This nuclear hypertrophy may represent an early neuronal reaction to Abeta or Tau, or a compensatory mechanism which forestalls the progression of AD and allows the brain to resist the development of dementia.

Spina S, Murrell JR, Huey ED, Wassermann EM, Pietrini P, Baraibar MA, Barbeito AG, Troncoso JC, Vidal R, Ghetti B, Grafman J. · Indiana Alzheimer Disease Center, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Neurology. · Pubmed #17202431 No free full text.

Abstract: BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). OBJECTIVE: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). METHODS: Patients underwent a single clinical assessment, MRI, and [(18)F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. RESULTS: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A-->G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A-->G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. CONCLUSIONS: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.

Driscoll I, Resnick SM, Troncoso JC, An Y, O'Brien R, Zonderman AB. · Laboratory of Personality and Cognition, National Institute on Aging, National Institutes of Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Ann Neurol. · Pubmed #17192929 No free full text.

Abstract: OBJECTIVE: Some individuals who are asymptomatic for dementia while alive have substantial Alzheimer's disease (AD) neuropathology at autopsy. We investigated whether cognitive trajectories differ between clinically normal elderly individuals with and without AD neuropathology and how they compare with trajectories of clinically impaired individuals before dementia diagnosis. METHODS: Eighty-one elderly participants in the Baltimore Longitudinal Study of Aging (BLSA) were followed prospectively with neurological and neuropsychological assessments before autopsy evaluation at death. Trajectories of cognitive change were estimated for a number of domains using cognitive data before a clinical diagnosis of dementia. RESULTS: Clinically normal elderly individuals with and without AD-type neuropathology have similar cognitive trajectories across different cognitive domains. In contrast, individuals with mild cognitive impairment/AD show steeper rates of longitudinal decline in several aspects of cognition compared with clinically normal elderly individuals regardless of whether the latter have AD neuropathology. Moreover, the cognitive differences between impaired and unimpaired groups can be detected years before a diagnosis of dementia. INTERPRETATION: Clinically normal individuals with and without AD neuropathology do not differ in rates of cognitive decline across a number of cognitive domains. Understanding the factors that protect some individuals with AD pathology from cognitive impairment may contribute to the maintenance of cognitive health in the elderly.

Riudavets MA, Rubio A, Cox C, Rudow G, Fowler D, Troncoso JC. · Department of Neuropathology and Ophthalmic Pathology, Armed Forces Institute of Pathology, Washington, DC, USA. · J Neuropathol Exp Neurol. · Pubmed #17146288 No free full text.

Abstract: Alzheimer disease is the most common dementia in older Americans, but its impact on blacks is not clearly understood. We examined prospectively 200 autopsy brains at the Office of the Chief Medical Examiner in Maryland and compared the frequency and severity of Alzheimer lesions in blacks and whites. Histologic sections of the hippocampus and entorhinal and neocortices were immunostained for Abeta and tau proteins. Subjects were genotyped for ApoE. Abeta deposits were rated as none, sparse, moderate, or frequent; tau lesions were rated into 4 groups corresponding to Braak scores; and Abeta angiopathy was classified as present or absent. Outcome scores were treated as ordinal variables and analyzed by proportional odds logistic regression. Abeta plaques were present in 60% of black males, 58% of white males, 74% of black females, and 74% of white females. Tau lesions were present in 96% of black males, 88% of white males, 96% of black females, and 96% of white females. Neither race nor gender was a significant factor in the frequency or severity of Alzheimer lesions, and ApoE4 increased the risk for Alzheimer lesions similarly in blacks and whites.

Zamora E, Handisurya A, Shafti-Keramat S, Borchelt D, Rudow G, Conant K, Cox C, Troncoso JC, Kirnbauer R. · Department of Pathology, Division of Neuropathology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USA. · J Immunol. · Pubmed #16888028 links to  free full text

Abstract: Immunization with amyloid-beta (Abeta) prevents the deposition of Abeta in the brain and memory deficits in transgenic mouse models of Alzheimer's disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of Abeta vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an Abeta vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1-9 aa of Abeta protein repetitively on the viral capsid surface (Abeta-VLP). This Abeta peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with Abeta-VLP were well tolerated and induced high-titer autoAb against Abeta, that inhibited effectively assembly of Abeta(1-42) peptides into neurotoxic fibrils in vitro. Following Abeta-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced Abeta deposits in the brain and increased numbers of activated microglia. Furthermore, Abeta-VLP vaccinated mice also showed increased levels of Abeta in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the Abeta-VLP vaccine induces an effective humoral immune response to Abeta and may thus form a basis to develop a safe and efficient immunotherapy for human AD.

Koliatsos VE, Kecojevic A, Troncoso JC, Gastard MC, Bennett DA, Schneider JA. · Department of Pathology, Division of Neuropathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Acta Neuropathol. · Pubmed #16758165 No free full text.

Abstract: Work on acute models of cortical injury has revealed a population of small GABAergic interneurons that are induced to increase their low constitutive expression of neuronal nitric oxide (NO) synthase (nNOS). In some cases, this activation may play a role in NO-mediated degeneration of pyramidal neurons. In this report, we explore the anatomy of various classes of cortical nNOS (+) (nitrergic) neurons, with emphasis on small interneurons, in the medial temporal lobe of subjects with Alzheimer's disease (AD) from two well-characterized cohorts, the Baltimore Longitudinal Study on Aging (BLSA) and the Religious Order Study (ROS). We find that small calbindin (+) cortical interneurons are induced to high levels of NADPHd/nNOS reactivity early in AD and abound in areas with emerging neurofibrillary pathology, that is, in entorhinal cortex in the beginning of the limbic stage of Braak, in hippocampal CA1 in the mature limbic stage and in temporal neocortex in the late limbic stage. This pattern was robust and significant in the younger of the two AD cohorts studied (BLSA), but persisted as a trend in the older cohort (ROS). In optimally prepared material, we find a significant correlation between numbers of these interneurons and markers of neuronal cell death, for example, caspase-3 activation. Our results show that small cortical inhibitory interneurons represent an extensive signaling system that is induced to higher levels of NADPHd/nNOS expression early in the paralimbic-limbic-neocortical sequence of AD progression. We propose that nNOS/NO signaling initiated in these interneurons can serve as a marker of early cortical injury in AD. The specific role played by inhibitory interneurons and NO in the elaboration of specific neuropathologies associated with AD, that is, Abeta and neurofibrillary deposits and cell death deserves further exploration in experimental animal models.

Stoltenberg M, Bruhn M, Søndergaard C, Doering P, West MJ, Larsen A, Troncoso JC, Danscher G. · Department of Neurobiology, Institute of Anatomy, University of Aarhus, 8000, Aarhus C, Denmark. · Histochem Cell Biol. · Pubmed #15981003 No free full text.

Abstract: An easy to perform autometallographic technique (AMG) for capturing zinc ions in Alzheimer plaques is presented. The possibility of visualizing loosely bound or free zinc ions in tissue by immersion autometallography (iZnS(AMG)) is a relatively recent development. The iZnS(AMG) staining is caused by zinc-sulphur nanocrystals created in 1-2 mm thick brain slices that are immersed in a 0.1% sodium sulphide, 3% glutaraldehyde phosphate buffered solution, the NeoTimm Solution (NTS), for 3 days. When the zinc-sulphur nanocrystals are subsequently silver-enhanced by autometallography, the plaques are readily identified as spheres of dark interlacing strands of different sizes, embedded in the pattern of zinc-enriched terminals. The zinc specificity of the iZnS(AMG) technique was tested by immersion of brain slides in the chelator DEDTC prior to the NTS immersion. The iZnS(AMG) detection of zinc ions is easily standardized and can be used in the quantification of plaques with stereological methods. This technique is the first to detect zinc in plaques in the cerebellum of transgenic PS1/APP mice and the first to detect zinc ions in plaques and dystrophic neurites at electron microscopical levels.

Pletnikova O, West N, Lee MK, Rudow GL, Skolasky RL, Dawson TM, Marsh L, Troncoso JC. · Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Ross Building 558, Baltimore, MD 21205, USA. · Neurobiol Aging. · Pubmed #15917102 No free full text.

Abstract: In order to understand better the neuropathological substrate of dementia in Parkinson's disease (PD) and to examine its interactions with Alzheimer's disease (AD), we examined autopsy brains from 21 cases of PD and Lewy body disease (LBD) with dementia. We separated brains in two groups according to the presence of Abeta deposits. In brains without Abeta, we found few or no Lewy bodies (LB) in the cerebral cortex. By contrast, in brains with Abeta, we observed significant increases in LB in the cerebral cortex (p < 0.01) and alpha-synuclein immunoreactive lesions in the cingulate cortex (p < 0.01). Immunoblots of alpha-synuclein from cingulate cortex in brains with Abeta showed significantly higher levels of insoluble alpha-synuclein compared to brains without Abeta. Our observations indicate that in cases of PD with dementia, the neocortex is not necessarily involved by LB. Furthermore, the presence of Abeta deposits in the cerebral cortex was associated with extensive alpha-synuclein lesions and higher levels of insoluble alpha-synuclein. This suggests that Abeta enhances the development of cortical alpha-synuclein lesions in cases of PD.

Mikolaenko I, Pletnikova O, Kawas CH, O'Brien R, Resnick SM, Crain B, Troncoso JC. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA. · J Neuropathol Exp Neurol. · Pubmed #15751230 No free full text.

Abstract: Alpha-synuclein (alpha-synuclein) lesions are characteristic of idiopathic Parkinson disease (PD) and other alpha-synucleinopathies. To study the frequency of alpha-synuclein lesions in normal aging and how frequently they coexist with lesions of Alzheimer disease (AD), we examined the autopsy brains from normal and demented subjects in the Baltimore Longitudinal Study of Aging (BLSA) (n = 117). We found that the overall frequency of alpha-synuclein lesions was 25%, with 100% in 7 cases of PD, 31.5% in 56 cases with AD lesions, and 8.3% among 36 older control brains. Among brains with AD lesions, the frequency of alpha-synuclein pathology was higher in those with higher scores for neuritic plaques, but not in those with higher scores for neurofibrillary tangles. Our observations indicate that alpha-synuclein lesions are uncommon in aged control subjects. Finally, the coexistence of Abeta amyloid and alpha-synuclein pathology in AD brains suggests that the pathogenic mechanism/s leading to the accumulation of Abeta and alpha-synuclein may be similar.

West MJ, Kawas CH, Stewart WF, Rudow GL, Troncoso JC. · Department of Neurobiology, Institute of Anatomy, Building 234, University Park, Aarhus 8000, Denmark. · Neurobiol Aging. · Pubmed #15312966 No free full text.

Abstract: In a previous study of hippocampal neurons in aging and AD [Lancet 344 (1994) 769], we demonstrated that the loss of neurons in the CA1 region was disease-specific and not related to aging. In the present study, we examined for loss of hippocampal neurons in preclinical AD, a period during which there are abundant amyloid deposits in the brain but no evidence of cognitive decline. We examined the postmortem brains of 33 subjects from the Baltimore Longitudinal Study of Aging and the Johns Hopkins Alzheimer's Disease Research Center. Using unbiased stereology, we estimated the total number of neurons in the granule cell layer, hilus, CA3-2, CA1, and subiculum of AD (n = 14) preclinical AD (n = 8), and age-matched control subjects (n = 11). The results from the present study confirm our previous finding of significant neuronal losses in the CA1 (48%), hilus (14%), and subiculum (24%) in AD [Lancet 344 (1994) 769]. However, we did not observe a significant loss of neurons in CA1 or any of the other subdivisions of the hippocampus in preclinical AD.

Blass DM, Hatanpaa KJ, Brandt J, Rao V, Steinberg M, Troncoso JC, Rabins PV. · Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Neurology. · Pubmed #15304580 No free full text.

Abstract: OBJECTIVE: To characterize the clinical course of pathologically diagnosed hippocampal sclerosis dementia (HSD). BACKGROUND: Dementia associated with HSD is incompletely characterized. Previous studies suggest similarities to both Alzheimer disease (AD) and frontotemporal dementia (FTD). METHODS: Case-control analysis of the clinical course of patients with HSD, FTD, and AD from a neuropathology autopsy series conducted by a university hospital. Case histories were reviewed. Cumulative prevalence of behavioral, cognitive, psychiatric, and language symptoms were compared between groups, as was time of symptom onset. Clinical diagnostic criteria for FTD and AD were applied to case histories. Sensitivity and specificity of clinical FTD diagnostic criteria (Report of the Work Group on FTD and Pick's disease) were computed. RESULTS: Cumulative prevalence of symptoms in HSD was most similar to that of FTD and differed from AD. Behavioral abnormalities such as decreased grooming and inappropriate behavior were more prevalent in HSD and FTD than AD. Hyperorality, inappropriate behavior, and decreased interest had earlier onset in HSD and FTD. Cognitive symptoms of disorientation, dyscalculia, apraxia, and agnosia were more prevalent in AD, as were psychiatric symptoms of hallucinations, delusions, and aggression. Most HSD patients met diagnostic criteria for FTD. Criteria sensitivity was 64.0% and specificity was 73.7%. CONCLUSIONS: FTD is a clinical syndrome associated with heterogeneous neuropathology. The clinical course of HSD is more similar to that of FTD than AD. These findings, together with the neuropathologic data presented in the accompanying article, support expanding the scope of FTD (Pick complex) to include HSD.

Mitchelmore C, Büchmann-Møller S, Rask L, West MJ, Troncoso JC, Jensen NA. · Laboratory of Mammalian Molecular Genetics, The Panum Institute 6.5, University of Copenhagen, 2200 Copenhagen N, Denmark. · Neurobiol Dis. · Pubmed #15207261 No free full text.

Abstract: Our understanding of the genes involved in Alzheimer's disease (AD) is incomplete. Using subtractive cloning technology, we discovered that the alpha/beta-hydrolase fold protein gene NDRG2 (NDRG family member 2) is upregulated at both the RNA and protein levels in AD brains. Expression of NDRG2 in affected brains was revealed in (1) cortical pyramidal neurons, (2) senile plaques and (3) cellular processes of dystrophic neurons. Overexpression of two splice variants encoding a long and short NDRG2 isoform in hippocampal pyramidal neurons of transgenic mice resulted in localization of both isoforms to dendritic processes. Taken together, our findings suggest that NDRG2 upregulation is associated with disease pathogenesis in the human brain and provide new insight into the molecular changes that occur in AD.

Chung KK, Thomas B, Li X, Pletnikova O, Troncoso JC, Marsh L, Dawson VL, Dawson TM. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Science. · Pubmed #15105460 links to  free full text

Abstract: Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.

Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP. · Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. · Proc Natl Acad Sci U S A. · Pubmed #14970312 links to  free full text

Abstract: Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid beta-peptide (Abeta) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to Abeta deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to Abeta induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with alpha-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by Abeta. Our findings suggest a sequence of events in the pathogenesis of AD in which Abeta induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.

Fonseca MI, Kawas CH, Troncoso JC, Tenner AJ. · Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA. · Neurobiol Dis. · Pubmed #14751769 No free full text.

Abstract: Complement has been postulated to contribute to inflammatory reactions associated with the neuropathology of Alzheimer's disease (AD). C1q, an initial component of the complement cascade, is associated with neuritic plaques and with neurons in the hippocampus of AD brain. Here, we report the presence of C1q in a cognitively intact subject, previously identified as preclinical AD. We compared in detail brain tissue of this preclinical case with a genetically related late-onset AD case. In the AD brain, C1q was typically associated with fibrillar Abeta plaques in frontal cortex and with plaques and neurons in the hippocampus. In the preclinical subject, C1q was abundantly present but it was cell-associated only, being primarily colocalized with neurons in both frontal cortex and hippocampus. However, no predominant cortical neuronal C1q localization was found in other preclinical cases or in Down's cases of different ages. Thus, it is possible that this neuronal-associated C1q reflects an early, but transient, response to injury that may modulate the progression of neurological dysfunction in AD.

Gastard MC, Troncoso JC, Koliatsos VE. · Division of Neuropathology, Department of Neurology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA. · Ann Neurol. · Pubmed #12953274 No free full text.

Abstract: We investigated the cleavage of caspase-3, a marker of apoptosis, in the medial temporal lobe of older subjects with minimal cognitive deficits and low CERAD/intermediate Braak scores, that is, clinicopathological descriptors of early Alzheimer's disease (AD). The activation of caspase-3 was studied with immunoprecipitation-mass spectroscopy and immunocytochemistry, including colocalization with paired helical filaments in the neuropil and perikarya. We found that caspase-3 is activated in the parahippocampal gyrus in subjects with mild AD and that this event is silenced in more advanced illness. Caspase-3 immunoreactivity has a tangle-like appearance that coevolves with paired helical filament pathology within neurons. We propose that activation of apoptosis may occur very early in the medial temporal lobe in AD.

Zemaitaitis MO, Kim SY, Halverson RA, Troncoso JC, Lee JM, Muma NA. · Department of Pharmacology, Loyola University Stritch School of Medicine, Maywood, Illinois 60153, USA. · J Neuropathol Exp Neurol. · Pubmed #12578227 No free full text.

Abstract: Transglutaminases catalyze the covalent cross-linking of substrate proteins to form insoluble protein complexes that are resistant to degradation. Our previous studies demonstrated that transglutaminase-induced cross-linking of tau proteins occurs in Alzheimer disease and progressive supranuclear palsy (PSP). The current study was designed to measure transglutaminase enzyme activity and the mRNA and protein levels of 3 transglutaminase isoforms that are expressed in human brain. Overall, transglutaminase activity was significantly increased in the globus pallidus (182% of control) and pons in PSP (171% of control) but not the occipital cortex (a region spared from pathology). Using a Spearman rank correlation test, we found that tissues with more transglutaminase-activity had more neurofibrillary tangles. Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.

Vehmas AK, Kawas CH, Stewart WF, Troncoso JC. · Department of Pathology, Neuropathology Division, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD 21205-2196, USA. · Neurobiol Aging. · Pubmed #12498966 No free full text.

Abstract: We examined the associations of postmortem neocortical immunoreactivities for microglia, astrocytes, Abeta and Tau with cognitive changes in clinically characterized subjects with pathological diagnoses (CERAD classification) of definite AD (9), possible AD (15) and age-matched controls (11). By measuring the fractional area (FA) of immunoreactivity, we found that Abeta deposits appear early in the pathogenesis of Abeta, but cannot account for cognitive decline. We found a significant increases in FA for microglia in possible AD cases (nondemented) compared to controls (P<0.05) and in FA for astrocytes in definite AD (demented) compared to possible AD (P<0.01). Tau immunoreactivity was observed only in the neuropil of definite AD cases (P<0.001). The significant increase in microglia between controls and AD possible cases suggests that activation of microglia occurs in the early pathogenesis of AD, whereas the significant association between astrocytic reaction and dementia, suggests that these cells play a role in the late stage of the disease, when dementia develops. Tau immunoreactivity appears as the strongest morphological correlate of dementia.

Vehmas AK, Borchelt DR, Price DL, McCarthy D, Wills-Karp M, Peper MJ, Rudow G, Luyinbazi J, Siew LT, Troncoso JC. · Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA. · DNA Cell Biol. · Pubmed #11788049 No free full text.

Abstract: Although the pathogenesis of Alzheimer's disease (AD) is not fully understood, growing evidence indicates that the deposition of beta-amyloid (Abeta) and the local reactions of various cell types to this protein play major roles in the development of the disease. Immunization with the Abeta 1-42 peptide has been reported to decrease Abeta deposits in the brains of mutant amyloid precursor protein (APP/V717F) transgenic (tg) mice (Schenk et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173-177). We have replicated this finding in APPswe/PS1DeltaE9 tg mice, which also develop Abeta deposits in the brain. The immunized animals developed high titers of antibodies against Abeta 1-42 in serum, and Abeta deposits in the brains were significantly reduced. Using surface-enhanced laser desorption/ionization (SELDI) mass spectrometry and ProteinChip((R)) technology, we detected trends toward increased soluble Abeta peptide in the brain and a decrease in assayable Abeta peptide in the serum of immunized compared with control animals. This last finding raises the possibility that anti-Abeta antibodies in the periphery sequester Abeta peptides or target them for degradation and in this way contribute to the enhanced Abeta clearance from the brain in immunized animals.

Gyure KA, Durham R, Stewart WF, Smialek JE, Troncoso JC. · Department of Neuropathy, Armed Forces Institute of Pathology, Washington, DC, USA. · Arch Pathol Lab Med. · Pubmed #11260621 No free full text.

Abstract: CONTEXT: Down syndrome patients who live to middle age invariably develop the neuropathologic features of Alzheimer disease, providing a unique situation in which to study the early and sequential development of these changes. OBJECTIVE: To study the development of amyloid deposits, senile plaques, astrocytic and microglial reactions, and neurofibrillary tangles in the brains of young individuals (<30 years of age) with Down syndrome. METHODS: Histologic and immunocytochemical study of a series of autopsy brains (n = 14, from subjects aged 11 months to 56 years, with 9 subjects <30 years) examined at the Office of the Chief Medical Examiner of the State of Maryland and The Johns Hopkins Hospital. RESULTS: The principal observations included the presence of intraneuronal Abeta immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of Abeta) and the formation of senile plaques and neurofibrillary tangles. CONCLUSIONS: We propose the following sequence of events in the development of neuropathologic changes of Alzheimer disease in Down syndrome: (1) intracellular accumulation of Abeta in neurons and astrocytes, (2) deposition of extracellular Abeta and formation of diffuse plaques, and (3) development of neuritic plaques and neurofibrillary tangles with activation of microglial cells.