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

Abstract

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 ...

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

“…74,75 One of these studies included a discovery microarray approach that identified a number of proteins that are differentially expressed in such subjects, including APP binding protein and regulators of apoptosis, trafficking, cytoskeletal structure, and cell-cycle proteins. 74 Work by Perez-Nievas et al 75 showed more fibrillar and oligomer-positive Ab plaques, increased p-tau oligomers, and glial activation in demented compared with nondemented subjects with underlying AD pathology. In another study, low molecular weight SDSstable Ab oligomers were associated with the postsynaptic density in patients with Alzheimer dementia but not in nondemented HPCs.…”

The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease

“…1 However, this theory fails to explain the discrepancy between amyloid plaque deposition and cogni tive impairment in patients with Alzheimer disease. 5 Clinico pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer disease pathology in their brains without experiencing de mentia. 5 Although the significance of plaque load for Al zheimer disease is still under debate and several groups found the pattern of amyloid plaques to be of limited rele vance for the neuropathological staging of Alzheimer dis ease, results from other laboratories showed a strong correl ation between counts of senile plaques in the hippocampus and cortex and memory function.…”

“…5 Clinico pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer disease pathology in their brains without experiencing de mentia. 5 Although the significance of plaque load for Al zheimer disease is still under debate and several groups found the pattern of amyloid plaques to be of limited rele vance for the neuropathological staging of Alzheimer dis ease, results from other laboratories showed a strong correl ation between counts of senile plaques in the hippocampus and cortex and memory function. Glial activation emerged as a likely mediator of neurotoxicity and altered cognition, providing further insight into factors and pathways poten tially involved in human susceptibility or resilience to Al zheimer disease.…”

“…1 Although it is not clear whether abnormal processing of the amyloid pre cursor protein (APP) is the initial cause or rather a late event in the pathophysiology of Alzheimer disease, 2 the generation of Aβ from its precursor protein APP induces oxidative stress and plays a critical role in the pathogenesis and advancement of the disease, producing neuronal injury and loss, inflamma tion and characteristic activation of microglia and astrocytic cells. [3][4][5][6] Together with aberrant Aβ deposits in the neuropil, a genetic basis is essential in influencing the onset and/or modifying the progression of the disease. 7 Genomic factors…”

Topological analyses in APP/PS1 mice reveal that astrocytes do not migrate to amyloid-β plaques

“…We next investigated whether the small repulsive force detected between astrocytes and plaques, strong enough to cause the nearest astrocytes to move a few microns, would disturb g(r) at heavier plaque loads. Whereas in APP/PS1 mice the percentage of brain covered by thioflavin or methoxy-labeled plaques can reach 1%, in humans it ranges between 0.8-6.0%, with an average of around 3% (11,12).…”