Faculty Bibliography

We recently identified Secernin-1 (SCRN1) as a novel amyloid plaque associated protein using localized proteomics. Immunohistochemistry studies confirmed that SCRN1 was present in plaque-associated dystrophic neurites and also revealed distinct and abundant co-localization with neurofibrillary tangles (NFTs). Little is known about the physiological function of SCRN1 and its role in Alzheimer's disease (AD) and other neurodegenerative diseases has not been studied. Therefore, we performed a comprehensive study of SCRN1 distribution in neurodegenerative diseases. Immunohistochemistry was used to map SCRN1 accumulation throughout the progression of AD in a cohort of 58 patients with a range of NFT pathology (Abundant NFT, n = 21; Moderate NFT, n = 22; Low/No NFT, n = 15), who were clinically diagnosed as having AD, mild cognitive impairment or normal cognition. SCRN1 accumulation was also examined in two cases with both Frontotemporal Lobar Degeneration (FTLD)-Tau and AD-related neuropathology, cases of Down Syndrome (DS) with AD (n = 5), one case of hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D) and other non-AD tauopathies including: primary age-related tauopathy (PART, [n = 5]), Corticobasal Degeneration (CBD, [n = 5]), Progressive Supranuclear Palsy (PSP, [n = 5]) and Pick's disease (PiD, [n = 4]). Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons at both early and late stages of AD. Similar results were observed in DS with AD and PART. However, SCRN1 did not co-localize with phosphorylated tau inclusions in CBD, PSP or PiD. Co-immunoprecipitation revealed that SCRN1 interacted with phosphorylated tau in human AD brain tissue. Together, these results suggest that SCRN1 is uniquely associated with tau pathology in AD, DS and PART. As such, SCRN1 has potential as a novel therapeutic target and could serve as a useful biomarker to distinguish AD from other tauopathies.

There are growing genetic, transcriptomic and proteomic data pointing to the complexity of Alzheimer's disease (AD) pathogenesis. Unbiased "omics" approaches are essential for the future development of effective AD research, which will need to be combined and personalized, given that multiple distinct pathways can drive AD pathology. It is essential to gain a better understanding of the AD pathogenesis subtype variety and to develop several distinct therapeutic approaches tailored to address this diversity, as well as the common presence of mixed pathologies. These nonmutually exclusive therapeutic approaches include the targeting of multiple toxic oligomeric species concurrently, targeting the apolipoprotein E/amyloid β interaction and the modulation of innate immunity, as well as more "out of the box" ideas such as targeting infectious agents that may play a role in AD.

The use of fixed fibroblasts from familial and sporadic Alzheimer's disease patients has previously indicated an upregulation of mitochondria-ER contacts (MERCs) as a hallmark of Alzheimer's disease. Despite its potential significance, the relevance of these results is limited because they were not extended to live neurons. Here we performed a dynamic in vivo analysis of MERCs in hippocampal neurons from McGill-R-Thy1-APP transgenic rats, a model of Alzheimer's disease-like amyloid pathology. Live FRET imaging of neurons from transgenic rats revealed perturbed 'lipid-MERCs' (gap width <10 nm), while 'Ca²⁺-MERCs' (10-20 nm gap width) were unchanged. In situ TEM showed no significant differences in the lipid-MERCs:total MERCs or lipid-MERCs:mitochondria ratios; however, the average length of lipid-MERCs was significantly decreased in neurons from transgenic rats as compared to controls. In accordance with FRET results, untargeted lipidomics showed significant decreases in levels of 12 lipids and bioenergetic analysis revealed respiratory dysfunction of mitochondria from transgenic rats. Thus, our results reveal changes in MERC structures coupled with impaired mitochondrial functions in Alzheimer's disease-related neurons.This article has an associated First Person interview with the first author of the paper.

BACKGROUND AND PURPOSE/OBJECTIVE:The basal forebrain contains multiple structures of great interest to emerging functional neurosurgery applications, yet many neuroradiologists are unfamiliar with this neuroanatomy because it is not resolved with current clinical MR imaging. MATERIALS AND METHODS/METHODS:= 13) to demonstrate and characterize the detailed anatomy of the basal forebrain using a clinical 3T MR imaging scanner. We measured the size of selected internal myelinated pathways and measured subthalamic nucleus size, oblique orientation, and position relative to the intercommissural point. RESULTS:= .084 and .047, respectively). Individual variability for the subthalamic nucleus was greatest for angulation within the sagittal plane (range, 15°-37°), transverse dimension (range, 2-6.7 mm), and most inferior border (range, 4-7 mm below the intercommissural plane). CONCLUSIONS:Direct identification of basal forebrain structures in multiple planes using the TSE T2 sequence makes this challenging neuroanatomy more accessible to practicing neuroradiologists. This protocol can be used to better define individual variations relevant to functional neurosurgical targeting and validate/complement advanced MR imaging methods being developed for direct visualization of these structures in living patients.