Inside Alzheimer brain with CLARITY: senile plaques, neurofibrillary tangles and axons in 3-D.
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ABSTRACT:
SUBMITTER: Ando K
PROVIDER: S-EPMC4131133 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Data from a large autopsy series were analyzed to address questions pertinent to primary age-related tauopathy (PART) and Alzheimer's disease (AD): what factors are associated with increased severity of neurofibrillary degeneration in brains that lack neuritic amyloid plaques?; is there an association between Apolipoprotein E (APOE) alleles and PART pathologic severity independent of amyloid-β (Aβ) deposits?; and, how do the stains used to detect plaques and tangles impact the experimental results? Neuropathologic data were evaluated from elderly research volunteers whose brain autopsies were performed at University of Kentucky Alzheimer's Disease Center (UK-ADC; N = 145 subjects). All of the included subjects' brains lacked neuritic amyloid plaques according to the CERAD diagnostic criteria and the average final MMSE score before death was 26.8±4.6 stdev. The study incorporated evaluation of tissue with both silver histochemical stains and immunohistochemical stains to compare results; the immunohistochemical stains (Aβ and phospho-tau) were scanned and quantified using digital pathologic methods. Immunohistochemical stains provided important advantages over histochemical stains due to sensitivity and detectability via digital methods. When AD-type pathology was in its presumed earliest phases, neocortical parenchymal Aβ deposits were associated with increased medial temporal lobe neurofibrillary tangles. The observation supports the NIA-AA consensus recommendation for neuropathologic diagnoses, because even these "diffuse" Aβ deposits signal that AD pathobiologic mechanisms are occurring. Further, the data were most compatible with the hypothesis that the APOEɛ4 allele exerts its effect(s) via driving Aβ deposition, i.e., an "upstream" influence, rather than being associated directly with Aβ- independent PART pathology.
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Project description:INTRODUCTION: Omics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer’s disease (AD) but the spatial relationships with plaques and tangles and APOE-linked differences remain unclear. METHODS: We performed laser capture microdissection of Ab plaques, the 50mm halo around them, tangles with the 50mm halo around them, and areas distant (>50mm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing. RESULTS: Ab plaques exhibited upregulated microglial (neuroinflammation) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Ab plaques had more differentially expressed genes than tangles. We identified a gradient Ab plaque>peri-plaque>tangle>distant for these changes. AD APOEe4 homozygotes had greater changes than APOEe3 across locations, especially within Ab plaques. DISCUSSION: Transcriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Ab plaques, and are exacerbated by the APOEe4 allele.
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Project description:Neurofibrillary tangles (NFT) and ?-amyloid plaques are the neurological hallmarks of both Alzheimer's disease and an unusual paralytic illness suffered by Chamorro villagers on the Pacific island of Guam. Many Chamorros with the disease suffer dementia, and in some villages one-quarter of the adults perished from the disease. Like Alzheimer's, the causal factors of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) are poorly understood. In replicated experiments, we found that chronic dietary exposure to a cyanobacterial toxin present in the traditional Chamorro diet, ?-N-methylamino-l-alanine (BMAA), triggers the formation of both NFT and ?-amyloid deposits similar in structure and density to those found in brain tissues of Chamorros who died with ALS/PDC. Vervets (Chlorocebus sabaeus) fed for 140 days with BMAA-dosed fruit developed NFT and sparse ?-amyloid deposits in the brain. Co-administration of the dietary amino acid l-serine with l-BMAA significantly reduced the density of NFT. These findings indicate that while chronic exposure to the environmental toxin BMAA can trigger neurodegeneration in vulnerable individuals, increasing the amount of l-serine in the diet can reduce the risk.
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