Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease

Cell type-specific changes identified by single-cell transcriptomics in Alzheimer’s disease

“…Leng et al [ 45 ] showed that RORB+ glutamatergic neurons are selectively depleted in the entorhinal cortex, but not in the superior frontal gyrus, evidence for layer- and subset-specific early-stage neurodegeneration in AD. Similarly, Otero-Garcia et al [ 43 ] used a novel partial cell body sorting technique to identify that a subset of neurons in layer 2/3, as well as a subset of deeper layer RORB+-positive neurons in the frontal cortex, are enriched among cells with higher abundance of intracellular AT8+ tau in their somata. In addition, these vulnerable sets of neurons share a common upregulation of genes encoding for synaptic and cytoskeletal proteins [ 43 ], as has been found in other snRNA-seq studies [ 40 , 44 ].…”

“…Similarly, Otero-Garcia et al [ 43 ] used a novel partial cell body sorting technique to identify that a subset of neurons in layer 2/3, as well as a subset of deeper layer RORB+-positive neurons in the frontal cortex, are enriched among cells with higher abundance of intracellular AT8+ tau in their somata. In addition, these vulnerable sets of neurons share a common upregulation of genes encoding for synaptic and cytoskeletal proteins [ 43 ], as has been found in other snRNA-seq studies [ 40 , 44 ]. This study also identified certain RORB+ neuronal subsets as being resistant to the accumulation of tau pathology, whereas the RORB+/PCP4+ subgroup preferentially accumulates tau; this suggests that not all projection neurons, even within the same cortical layer, are equally vulnerable.…”

“…Single-cell studies have also linked neuronal profiles with NEFL and APOE, two genes heavily studied in AD. Multiple snRNA-seq studies have reported the loss of neurons with high expression of NEFL in AD [ 28 , 42 , 43 ]. This corroborates prior histological studies showing alterations in NEFL distribution in intact tissue in individuals with mild and severe AD [ 64 , 65 ].…”

Towards elucidating disease-relevant states of neurons and glia by CRISPR-based functional genomics

“…On the other hand, many neurodegenerative diseases are thought to be driven by the toxic aggregation of specific proteins; therefore, a reduction in the level of those proteins may be therapeutically beneficial. Furthermore, the accumulation of toxic protein aggregates or other pathological products in a cell could be associated with disease-associated cell states [68,69]. Several genetic screens have uncovered positive and negative regulators of the levels of disease-relevant proteins.…”

“…Converging with these insights, single-cell sequencing of mouse models of AD has uncovered disease-associated microglia (DAM) [4][5][6] and astrocytes (DAA) [7]; both DAM and DAA appear to be driven by amyloid pathology. Beyond mouse models, single-cell profiling of human AD brain tissue has identified a variety of disease-associated perturbations in neurons as well as glia [5,[8][9][10][11][12][13][14][15]. It is likely that in human AD, multiple disease-associated microglial states exist [9,11], which may partially explain the limited overlap of DAM markers with upregulated genes in microglia found in human AD brain tissue [5].…”