Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β

Koffie, Robert M.; Hashimoto, Tadafumi; Tai, Hwan‐Ching; Kay, Kevin; Serrano-Pozo, Alberto; Joyner, Daniel; Hou, Steven S.; Kopeikina, Katherine J.; Frosch, Matthew P.; Lee, Virginia M.; Holtzman, David M.; Hyman, Bradley T.; Spires‐Jones, Tara L.

doi:10.1093/brain/aws127

Cited by 284 publications

(305 citation statements)

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“…Only when we used immunohistochemistry and a conformer-specific antibody (NAB61), we found a significantly higher burden of oligomeric amyloid-b deposits in demented Alzheimer's disease than in high probability mismatches. NAB61-positive amyloid-b oligomeric deposits were mainly seen decorating the periphery and core of fibrillar plaques, as noted in previous human and mouse studies (Koffie et al, 2009;DaRocha-Souto et al, 2011;Koffie et al, 2012). Of note, NAB61 was effective in normalizing cognition in immunotherapy experiments in transgenic mice suggesting that it can detect neurotoxic amyloid-b species (Lee et al, 2006).…”

Section: Discussionsupporting

confidence: 73%

Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology

Perez‐Nievas¹,

Stein²,

Tai³

et al. 2013

Brain

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326

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Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases. Quantification of amyloid-b plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloidb and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-b plaques and tangles to those found in demented Alzheimer's cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-Spositive plaques and of oligomeric amyloid-b deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-b and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-b species-monomers, dimers and higher molecular weight oligomers-in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-b plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-b and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer's pathology. Amyloid-b deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-b assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human ...

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Section: Discussionsupporting

confidence: 73%

Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology

Perez‐Nievas¹,

Stein²,

Tai³

et al. 2013

Brain

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326

310

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“…24 Neurotoxic and synaptotoxic effects of Aβ oligomers per se have also been observed. [42][43][44] Thus, the interstitial Aβ could influence the secondary injury cascade after TBI. In addition, alternate splicing of the APP molecule may occur and generation of other Aβ species than Aβ42 evaluated in our present report is possible.…”

Section: Discussionmentioning

confidence: 99%

Monitoring of β-Amyloid Dynamics after Human Traumatic Brain Injury

Marklund

Farrokhnia

Hånell

et al. 2014

Journal of Neurotrauma

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Epidemiological evidence links severe or repeated traumatic brain injury (TBI) to the development of Alzheimer's disease (AD). Accumulation of amyloid precursor protein (APP) occurs with high frequency after TBI, particularly in injured axons, and APP may be cleaved to amyloid-β (Aβ) peptides playing key pathophysiological roles in AD. We used cerebral microdialysis (MD) to test the hypothesis that interstitial Aβ levels are altered following TBI and are related to the injury type, cerebral energy metabolism, age of the patient, and level of consciousness. In the present report, we evaluated 10 mechanically ventilated patients (7 male, 3 female, ages 18-76 years) with a severe TBI, who had intracranial pressure and MD monitoring. Each MD sample was analyzed for hourly routine energy metabolic biomarkers (MD-lactate, MD-pyruvate, MD-glucose, and MD-lactate/pyruvate ratio), cellular distress biomarkers (MD-glutamate, MD-glycerol), and MD-urea. The remaining MD samples were analyzed for Aβ1-40 (Aβ40; n=765 samples) and Aβ1-42 (Aβ42; n=765 samples) in pooled 2 h fractions up to 14 days post-injury, using the Luminex xMAP technique, allowing detection with high temporal resolution of the key Aβ peptides Aβ40 and Aβ42. Data are presented using medians and 25th and 75th percentiles. Both Aβ40 and Aβ42 were consistently higher in patients with predominately diffuse axonal injury compared with patients with focal TBI at days 1-6 post- injury, Aβ42 being significantly increased at 113-116 h post-injury (p<0.05). The Aβ levels did not correlate with the interstitial energy metabolic situation, age of the patient, or the level of consciousness. These results support that interstitial generation of potentially toxic Aβ species may occur following human TBI, particularly related to axonal injury.

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“…Suggested mechanisms by which the ApoE4 may affect amyloid deposition include increased Aβ fibrillisation27 and aggregation28 as well as decreased Aβ clearance 11. In addition, ApoE4 may preferentially direct Aβ to synapses, leading to greater synaptic loss in ɛ4 carriers 29. These data suggest a direct and isoform-dependent interaction between ApoE and amyloid contributing to AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients

Lehmann

Ghosh

Madison

et al. 2013

Journal of Neurology, Neurosurgery & Psychiatry

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Background ApoE4 has been associated with an increased risk of Alzheimer’s disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and glucose metabolism across different clinical AD syndromes is not well understood. We aimed to assess the relationship between amyloid deposition, glucose metabolism and ApoE4 genotype in a clinically heterogeneous population of AD patients. Methods Fifty-two patients with probable AD (NIA-AA) underwent [11C]Pittsburgh compound B (PIB) and [18F]fluorodeoxyglucose (FDG) PET scans. All patients had positive PIB-PET scans. 23 were ApoE4+ (14 heterozygous, 9 homozygous) and 29 were ApoE4−. Groups consisted of language-variant AD, visual-variant AD, and AD patients with amnestic and dysexecutive deficits. 52 healthy controls were included for comparison. FDG and PIB uptake was compared between groups on a voxel-wise basis and in regions-of-interest. Results Whilst PIB patterns were diffuse in both patient groups, ApoE4− patients showed higher PIB uptake than ApoE4+ patients across the cortex. Higher PIB uptake in ApoE4− patients was particularly significant in right lateral frontotemporal regions. In contrast, similar patterns of hypometabolism relative to controls were found in both patient groups, mainly involving lateral temporoparietal cortex, precuneus, posterior cingulate cortex, and middle frontal gyrus. Comparing patient groups, ApoE4+ subjects showed greater hypometabolism in bilateral medial temporal and right lateral temporal regions, and ApoE4− patients showed greater hypometabolism in cortical areas including supplementary motor cortex and superior frontal gyrus. Conclusions ApoE4+ AD patients showed lower global amyloid burden and greater medial temporal hypometabolism compared to matched ApoE4− patients. These findings suggest that ApoE4 may increase susceptibility to molecular pathology and modulate the anatomic pattern of neurodegeneration in AD.

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Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β

Cited by 284 publications

References 58 publications

Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology

Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology

Monitoring of β-Amyloid Dynamics after Human Traumatic Brain Injury

Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients

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