Alzheimer's Disease
Multifaceted roles of APOE in Alzheimer disease
For the past three decades, apolipoprotein E (APOE) has been known as the single greatest genetic modulator of sporadic Alzheimer disease (AD) risk, influencing both the average age of onset and the lifetime risk of developing AD. The APOEε4 allele significantly increases AD risk, whereas the ε2 allele is protective relative to the most common ε3 allele. However, large differences in effect size exist across ethnoracial groups that are likely to depend on both global genetic ancestry and local genetic ancestry, as well as gene-environment interactions. Although early studies linked APOE to amyloid-β - one of the two culprit aggregation-prone proteins that define AD - in the past decade, mounting work has associated APOE with other neurodegenerative proteinopathies and broader ageing-related brain changes, such as neuroinflammation, energy metabolism failure, loss of myelin integrity and increased blood-brain barrier permeability, with potential implications for longevity and resilience to pathological protein aggregates. Novel mouse models and other technological advances have also enabled a number of therapeutic approaches aimed at either attenuating the APOEε4-linked increased AD risk or enhancing the APOEε2-linked AD protection. This Review summarizes this progress and highlights areas for future research towards the development of APOE-directed therapeutics.
Read MoreNeurofibrillary tangle-bearing neurons have reduced risk of cell death in mice with Alzheimer's pathology
A prevailing hypothesis is that neurofibrillary tangles play a causal role in driving cognitive decline in Alzheimer’s disease (AD) because tangles correlate anatomically with areas that undergo neuronal loss. We used two-photon longitudinal imaging to directly test this hypothesis and observed the fate of individual neurons in two mouse models. At any time point, neurons without tangles died at >3 times the rate as neurons with tangles. Additionally, prior to dying, they became >20% more distant from neighboring neurons across imaging sessions. Similar microstructural changes were evident in a population of non-tangle-bearing neurons in Alzheimer’s donor tissues. Together, these data suggest that nonfibrillar tau puts neurons at high risk of death, and surprisingly, the presence of a tangle reduces this risk. Moreover, cortical microstructure changes appear to be a better predictor of imminent cell death than tangle status is and a promising tool for identifying dying neurons in Alzheimer’s.
Read MoreSomatic genomic changes in single Alzheimer's disease neurons
Dementia in Alzheimer’s disease correlates with progressive neurodegeneration, but the precise causes of neuronal dysfunction remain unclear. This study analyzed single-cell whole-genome sequencing of 319 neurons from Alzheimer’s patients and controls, revealing increased somatic DNA mutations in affected neurons with distinct molecular signatures. While normal neurons accumulate mutations via age-related “clock-like” patterns, Alzheimer’s neurons exhibit additional oxidative DNA damage. These mutations affect coding regions and likely disrupt neuronal function, suggesting that genomic damage contributes to disease progression and neuronal impairment.
Read MoreUbiquitin-Proteasome System Dysregulation in Alzheimer's Disease Impacts Protein Abundance
Alzheimer’s disease (AD) is a relentlessly progressive, fatal neurodegenerative disorder associated with widespread aberrant proteomic changes. The full extent of protein dysfunctions in AD and their impact on cellular physiology remains unknown. Here, we used plexDIA, an approach that parallelizes the acquisition of samples and peptides, to characterize proteomic changes in AD. Using human dorsolateral prefrontal cortex tissue, we identified 281 differentially abundant proteins in AD. By systematically analyzing cellular compartment-specific shifts in protein abundance, we identified an AD-specific decrease in levels of the 20S proteasome, the catalytic core of the cell’s primary protein degradation pathway. This alteration was accompanied by widespread decreases in proteasome subunit stoichiometries. Many proteasome substrate proteins were negatively correlated with 20S levels and increased in AD, suggesting that reduced 20S levels leads to abnormal protein accumulation. By analyzing proteins increased in AD, we identify key properties of such proteins. Namely, they have highly specific subcellular localizations and fast degradation rates, they contain signal sequences that allow them to be targeted for proteasomal degradation, and they are targeted by quality control pathways that recognize mislocalized proteins. Furthermore, we identify coherent sets of ubiquitin system enzymes, proteins that target substrates for proteasomal degradation, whose levels robustly discriminate AD from non-AD samples. One subset exhibited consistent increases in AD, while another exhibited consistent decreases, revealing complex alterations to the ubiquitin system in AD. Taken together, our results suggest that decreased ubiquitin-proteasome system capacity and impaired clearance of short-lived and mislocalized proteins contribute substantially to proteopathic burden in AD.
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