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1.
J Neuropathol Exp Neurol ; 69(12): 1201-9, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21107133

ABSTRACT

Aquaporins have recently been identified as protein channels involved in water transport. These channels may play a role in the edema formation and alterations in microvascular function observed in Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). We investigated the expression of aquaporin 1 (AQP1) and aquaporin 4 (AQP4) in 24 human autopsy brains consisting of 18 with AD and varying degrees of CAA and 6 with no pathologic abnormalities using immunohistochemistry. In cases of AD and CAA, there was enhanced AQP4 expression compared with the age- and sex-matched controls. Aquaporin 4 immunoreactivity was prominent at the cerebrospinal fluid and brain interfaces, including subpial, subependymal, pericapillary, and periarteriolar spaces. Aquaporin 1 expression in AD and CAA cases was not different from that in age- and sex-matched controls. Double labeling studies demonstrated that both AQP1 and 4 were localized to astrocytes. Both enhanced AQP4 expression and its unique staining pattern suggest that these proteins may be important in the impaired water transport observed in AD and CAA.


Subject(s)
Aquaporin 1/biosynthesis , Aquaporin 4/biosynthesis , Brain/metabolism , Cerebral Amyloid Angiopathy/metabolism , Gene Expression Regulation , Adult , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Brain/pathology , Cerebral Amyloid Angiopathy/pathology , Female , Humans , Male
2.
Hum Pathol ; 41(11): 1601-8, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20688356

ABSTRACT

The occurrence and progression of cerebral ß-amyloid angiopathy and ß-amyloid plaques in sporadic Alzheimer's disease may be attributed to aging-related deficiencies in ß-amyloid drainage along cerebral perivascular pathways. To elucidate high-definition characteristics of cerebral ß-amyloid deposition, we performed immunogold silver staining for ß-amyloid-40 and ß-amyloid-42 on semithin LR White-embedded tissue sections from 7 Alzheimer's disease/severe cerebral ß-amyloid angiopathy, 9 Alzheimer's disease/mild cerebral ß-amyloid angiopathy, 5 old control, and 4 young control autopsy brains. In vessel walls, ß-amyloid-40 and ß-amyloid-42 deposits were unevenly distributed along the adventitia and among the medial smooth muscle cells. ß-Amyloid-40 immunoreactivity appeared greater than that of ß-amyloid-42 in vessel walls, with ß-amyloid-42 being preferentially located on their abluminal regions. In capillary walls, either ß-amyloid-40 or ß-amyloid-42 deposits or both were present in 6 of 7 severe cerebral ß-amyloid angiopathy and in 1 of 9 mild cerebral ß-amyloid angiopathy cases, with a marked variation in thickness and focally abluminal excrescences. In 5 of 7 severe cerebral ß-amyloid angiopathy cases, a subset of ß-amyloid-laden capillaries revealed either ß-amyloid-40 or ß-amyloid-42 deposits or both radiating from their walls into the surrounding neuropil ("pericapillary deposits"). No vascular ß-amyloid-40 or ß-amyloid-42 deposits were observed in any of the controls. In conclusion, the patterns of ß-amyloid-42 and ß-amyloid-40 immunoreactivity in vessel walls suggest that ß-amyloid deposits occur in the vascular basement membranes along cerebral perivascular drainage pathways, extending from cortical capillaries to leptomeningeal arteries. The presence of pericapillary ß-amyloid deposits suggests that a subset of ß-amyloid plaques originate from ß-amyloid-laden capillaries, particularly in Alzheimer's disease brains that exhibit preferential capillary involvement by cerebral ß-amyloid angiopathy.


Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Cerebral Amyloid Angiopathy/pathology , Peptide Fragments/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Brain/blood supply , Capillaries/metabolism , Capillaries/pathology , Cerebral Amyloid Angiopathy/metabolism , Female , Humans , Male , Middle Aged , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Staining and Labeling , Young Adult
3.
Hum Mol Genet ; 19(16): 3233-53, 2010 Aug 15.
Article in English | MEDLINE | ID: mdl-20530642

ABSTRACT

Advances in genomics and proteomics permit rapid identification of disease-relevant genes and proteins. Challenges include biological differences between animal models and human diseases, high discordance between DNA and protein expression data and a lack of experimental models to study human complex diseases. To overcome some of these limitations, we developed an integrative approach using animal models, postmortem human material and a combination of high-throughput microarray methods to identify novel molecular markers of amyotrophic lateral sclerosis (ALS). We used laser capture microdissection coupled with microarrays to identify early transcriptome changes occurring in spinal cord motor neurons or surrounding glial cells. Two models of familial motor neuron disease, SOD1(G93A) and TAU(P301L), transgenic mice were used at the presymptomatic stage. Identified gene expression changes were predominantly model-specific. However, several genes were regulated in both models. The relevance of identified genes as clinical biomarkers was tested in the peripheral blood transcriptome of presymptomatic SOD1(G93A) animals using custom-designed ALS microarray. To confirm the relevance of identified genes in human sporadic ALS (SALS), selected corresponding protein products were examined by high-throughput immunoassays using tissue microarrays constructed from human postmortem spinal cord tissues. Genes that were identified by these experiments and located within a linkage region associated with familial ALS/frontotemporal dementia were sequenced in several families. This large-scale gene and protein expression study pointing to distinct molecular mechanisms of TAU- and SOD1-induced motor neuron degeneration identified several new SALS-relevant proteins (CNGA3, CRB1, OTUB2, MMP14, SLK, DDX58, RSPO2) and putative blood biomarkers, including Nefh, Prph and Mgll.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Biomarkers/analysis , Gene Expression Profiling/methods , Oligonucleotide Array Sequence Analysis/methods , Tissue Array Analysis/methods , Adult , Aged , Aged, 80 and over , Amyotrophic Lateral Sclerosis/genetics , Animals , Disease Models, Animal , Female , Genetic Predisposition to Disease/genetics , Humans , Immunohistochemistry , Male , Mice , Mice, Transgenic , Middle Aged , Motor Neuron Disease/genetics , Motor Neuron Disease/metabolism , Mutation , Postmortem Changes , Proteomics/methods , Reverse Transcriptase Polymerase Chain Reaction , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Superoxide Dismutase-1 , tau Proteins/genetics , tau Proteins/metabolism
4.
Acta Neuropathol ; 119(3): 291-302, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19937043

ABSTRACT

Neuroimaging with iron-sensitive MR sequences [gradient echo T2* and susceptibility-weighted imaging (SWI)] identifies small signal voids that are suspected brain microbleeds. Though the clinical significance of these lesions remains uncertain, their distribution and prevalence correlates with cerebral amyloid angiopathy (CAA), hypertension, smoking, and cognitive deficits. Investigation of the pathologies that produce signal voids is necessary to properly interpret these imaging findings. We conducted a systematic correlation of SWI-identified hypointensities to tissue pathology in postmortem brains with Alzheimer's disease (AD) and varying degrees of CAA. Autopsied brains from eight AD patients, six of which showed advanced CAA, were imaged at 3T; foci corresponding to hypointensities were identified and studied histologically. A variety of lesions was detected; the most common lesions were acute microhemorrhage, hemosiderin residua of old hemorrhages, and small lacunes ringed by hemosiderin. In lesions where the bleeding vessel could be identified, ß-amyloid immunohistochemistry confirmed the presence of ß-amyloid in the vessel wall. Significant cellular apoptosis was noted in the perifocal region of recent bleeds along with heme oxygenase 1 activity and late complement activation. Acutely extravasated blood and hemosiderin were noted to migrate through enlarged Virchow­Robin spaces propagating an inflammatory reaction along the local microvasculature; a mechanism that may contribute to the formation of lacunar infarcts. Correlation of imaging findings to tissue pathology in our cases indicates that a variety of CAA-related pathologies produce MR-identified signal voids and further supports the use of SWI as a biomarker for this disease.


Subject(s)
Cerebral Amyloid Angiopathy/pathology , Dementia/pathology , Aged , Alzheimer Disease/pathology , Blood Vessels/pathology , Brain Ischemia/etiology , Brain Ischemia/pathology , Cerebral Amyloid Angiopathy/metabolism , Coloring Agents , Complement C6/metabolism , Disease Progression , Dissection , Female , Fluorescent Dyes , Hemosiderin/metabolism , Humans , Image Processing, Computer-Assisted , Immunohistochemistry , Inflammation/pathology , Intracranial Hemorrhages/pathology , Magnetic Resonance Imaging , Male , Nerve Tissue Proteins/metabolism
5.
Brain Pathol ; 20(2): 459-67, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19725828

ABSTRACT

Cerebral amyloid angiopathy (CAA) is common in elderly individuals, especially those affected with Alzheimer's disease. Eighteen brains with severe SCAA (SCAA) were compared with 21 brains with mild CAA (MCAA) to investigate whether the presence of SCAA in the brains of demented patients was associated with a higher burden of old microinfarcts than those with MCAA. Immunohistochemistry for CD68 was employed to highlight old microinfarcts in tissue blocks from various brain regions. Old microinfarcts, manually counted by light microscopy, were present in 14 of 18 SCAA brains and in 7 of 21 MCAA brains (P = 0.01, two-tailed Fisher's exact test). The average number of old microinfarcts across geographic regions in each brain ranged from 0 to 1.95 (mean rank 24.94, sum of ranks 449) in the SCAA group, and from 0 to 0.35 (mean rank 15.76, sum of ranks 331) in the MCAA group (P = 0.008, two-tailed Mann-Whitney U-test). Frequent old microinfarcts in demented individuals with severe CAA may contribute a vascular component to the cognitive impairment in these patients.


Subject(s)
Amyloid beta-Peptides/metabolism , Brain Infarction/pathology , Brain/pathology , Cerebral Amyloid Angiopathy/pathology , Aged , Aged, 80 and over , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Brain/metabolism , Brain Infarction/complications , Brain Infarction/metabolism , Cardiovascular Diseases/complications , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Cerebral Amyloid Angiopathy/complications , Cerebral Amyloid Angiopathy/metabolism , Cerebrovascular Disorders/complications , Cerebrovascular Disorders/metabolism , Cerebrovascular Disorders/pathology , Female , Humans , Immunohistochemistry , Male , Middle Aged , Nerve Fibers, Myelinated/metabolism , Nerve Fibers, Myelinated/pathology , Nerve Fibers, Unmyelinated/metabolism , Nerve Fibers, Unmyelinated/pathology , Severity of Illness Index
6.
Arch Neurol ; 66(4): 448-57, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19364929

ABSTRACT

BACKGROUND: The sortilin-related receptor SorLA/LR11 (LR11) is a transmembrane neuronal sorting protein that reduces beta-amyloid precursor protein trafficking to secretases, notably BACE1 that generates beta-amyloid, the principal component of senile plaques in Alzheimer disease (AD). LR11 protein is reduced in patients with late-onset AD, and LR11 polymorphisms have been associated with late-onset AD. OBJECTIVE: T o detect soluble LR11 and APP in cerebrospinal fluid (CSF) from patients with AD and control subjects, as (like beta-amyloid precursor protein) LR11 is cleaved near the membrane to release a large N-terminal fragment that is secreted to media from cultured cells. DESIGN: Case-control study. SETTING: Academic research. PARTICIPANTS: Patients with AD and control subjects. MAIN OUTCOME MEASURES: We evaluated CSF LR11, beta-amyloid precursor protein, and apolipoprotein E levels by Western blot in lumbar and postmortem CSF samples. RESULTS: LR11 levels were detectable and stable during 6 months in the CSF of patients with AD. LR11 levels were significantly reduced in lumbar samples from patients with mild to moderate probable AD, as well as in ventricular CSF from patients with autopsy-confirmed AD (predominantly Braak stage III-IV). Bivariate analysis with beta-amyloid 42 and LR11 levels improved diagnostic specificity for AD. Reduced LR11 levels are significantly correlated with soluble beta-amyloid precursor protein but not apolipoprotein E levels. CONCLUSION: Reduced LR11 levels in CSF of patients with AD may have potential as a diagnostic biomarker for patients with LR11 deficits that promote beta-amyloid production or as an index of therapeutic response in late-onset AD.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Brain/metabolism , LDL-Receptor Related Proteins/cerebrospinal fluid , LDL-Receptor Related Proteins/genetics , Membrane Transport Proteins/cerebrospinal fluid , Membrane Transport Proteins/genetics , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/cerebrospinal fluid , Apolipoproteins E/cerebrospinal fluid , Blotting, Western , Brain/pathology , Case-Control Studies , Cell Line , Gene Expression Regulation/genetics , Humans , Neurofibrillary Tangles/pathology , Peptide Fragments/cerebrospinal fluid , Plaque, Amyloid/pathology , Predictive Value of Tests , Reference Values
7.
Neurobiol Aging ; 28(9): 1381-7, 2007 Sep.
Article in English | MEDLINE | ID: mdl-16828202

ABSTRACT

There are few studies on the clinical and neurochemical correlates of postsynaptic cholinergic dysfunction in Alzheimer's disease (AD). We have previously found that attenuation of guanine nucleotide-binding (G-) protein coupling to muscarinic M(1) receptors in the neocortex was associated with dementia severity. The present study aims to study whether this loss of M(1)/G-protein coupling is related to alterations in signaling kinases and NMDA receptors. Postmortem frontal cortices of 22 AD subjects and 12 elderly controls were obtained to measure M(1) receptors, M(1)/G-protein coupling, NMDA receptors as well as protein kinase C (PKC) and Src kinase activities. We found that the extent of M(1)/G-protein coupling loss was correlated with reductions in PKC activity and NMDA receptor density. In contrast, Src kinase activity was neither altered nor associated with M(1)/G-protein coupling. Given the well established roles of neuronal PKC signaling and NMDA receptor function in cognitive processes, our results lend further insight into the mechanisms by which postsynaptic cholinergic dysfunction may underlie the cognitive features of AD, and suggest alternative therapeutic targets to cholinergic replacement.


Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Brain/metabolism , Glutamic Acid/deficiency , Protein Kinase C/metabolism , Receptor, Muscarinic M1/metabolism , Aged , Aged, 80 and over , Brain/cytology , Brain/drug effects , Brain Chemistry/drug effects , Case-Control Studies , Dizocilpine Maleate/pharmacokinetics , Drug Interactions , Excitatory Amino Acid Antagonists/pharmacokinetics , Female , Humans , Male , Muscarinic Antagonists/pharmacokinetics , Pirenzepine/pharmacokinetics , Postmortem Changes , Radioligand Assay/methods , src-Family Kinases/metabolism
8.
Neuron ; 51(5): 549-60, 2006 Sep 07.
Article in English | MEDLINE | ID: mdl-16950154

ABSTRACT

Neurofibrillary tangles (NFT) containing tau are a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). NFT burden correlates with cognitive decline and neurodegeneration in AD. However, little is known about mechanisms that protect against tau-induced neurodegeneration. We used a cross species functional genomic approach to analyze gene expression in multiple brain regions in mouse, in parallel with validation in Drosophila, to identify tau modifiers, including the highly conserved protein puromycin-sensitive aminopeptidase (PSA/Npepps). PSA protected against tau-induced neurodegeneration in vivo, whereas PSA loss of function exacerbated neurodegeneration. We further show that human PSA directly proteolyzes tau in vitro. These data highlight the utility of using both evolutionarily distant species for genetic screening and functional assessment to identify modifiers of neurodegeneration. Further investigation is warranted in defining the role of PSA and other genes identified here as potential therapeutic targets in tauopathy.


Subject(s)
Aminopeptidases/metabolism , Brain/enzymology , Nerve Degeneration/enzymology , Tauopathies/genetics , tau Proteins/metabolism , Animals , Blotting, Northern , Blotting, Western , Brain/pathology , Drosophila , Gene Expression Profiling , Humans , Immunohistochemistry , In Situ Hybridization , Mice , Mice, Transgenic , Nerve Degeneration/pathology , Neurofibrillary Tangles/enzymology , Neurofibrillary Tangles/pathology , Oligonucleotide Array Sequence Analysis , Tauopathies/enzymology , Tauopathies/pathology , tau Proteins/genetics
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