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.

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.

Background: Alzheimer's disease (AD) is the most common form of dementia affecting 5.7 million individuals in the U.S. alone. While treatment approaches have predominantly focused on the reduc-tion of amyloid beta plaques, there has been a concerted shift to also target tau pathology, another major pathological marker of AD. There is no current treatment for AD, however profound efforts have been made in developing an immunotherapy approach. We have focused on activating Toll-like receptor 9 (TLR9), a stimulatory receptor of the innate immune system, in attempts to ameliorate the immune system's dysfunctional clearance. Our earlier studies revealed that stimulation of the innate immunity via TLR9 agonist, CpG ODN, in 3xTg-AD mice can alleviate all pathological hallmarks of AD (Ab, tau, CAA) and improve behavioral deficits without toxicity. Given the importance of tau related pathology, we designed an experiment to more directly determine the effect of CpG-ODN on tau pathology. This was done through rTg4510 mice, a tauopathy mouse model which develops robust forebrain tangle pathology without concurrent amyloid pathology.
Method(s): The rTg4510 mice were injected with either the TLR9 agonist Class B CpG-ODN or saline at monthly intervals (3 to 11 months of age). After the treatment period, immunohistochemistry and biochemical analyses (western blot) were performed. Peripheral immune response analyses (Th1/Th2 Luminex technology) are underway.
Result(s): Histological evaluation of CpG-ODN effect on hippo-campal and cortical brain regions revealed region specific reductions in PHF1 and MC1 immunoreactivity in CpG-ODN treated animals. Preliminary western blot analyses showed a significant reduction in total PHF1 phospho-tau levels (low-speed supernatant fraction) in the CpG-ODN-treated group in comparison to the saline-treated animals. Additionally, CpG-ODN treatment was not associated with increased insoluble tau pathology in sarcosyl fractions. Unlike previous attempts to simulate innate immunity, our method of immunomodulation demonstrated a modest, yet beneficial, effect on tau related pathology.
Conclusion(s): Overall, the present findings, together with our earlier research, demonstrate promising preclinical evidence for the potential use of TLR9 ligand CpG ODN as a disease modifying drug for Alzheimer's disease and other tau related dementias

BACKGROUND AND PURPOSE/OBJECTIVE:The brain stem is compactly organized with life-sustaining sensorimotor and autonomic structures that can be affected by numerous pathologies but can be difficult to resolve on conventional MR imaging. MATERIALS AND METHODS/METHODS:We applied an optimized TSE T2 sequence to washed postmortem brain samples to reveal exquisite and reproducible brain stem anatomic MR imaging contrast comparable with histologic atlases. This resource-efficient approach can be performed across multiple whole-brain samples with relatively short acquisition times (2 hours per imaging plane) using clinical 3T MR imaging systems. RESULTS:< .10). CONCLUSIONS:Compared with traditional atlases, multiplanar MR imaging contrast has advantages for learning and retaining brain stem anatomy for clinicians and trainees. Direct TSE MR imaging sequence discrimination of brain stem anatomy can help validate other MR imaging contrasts, such as diffusion tractography, or serve as a structural template for extracting quantitative MR imaging data in future postmortem investigations.

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that modify extracellular matrix components and play crucial roles in development and numerous diseases. ADAMTS18 is a member of the ADAMTS family, and genome-wide association studies made an initial association of ADAMTS18 with white matter integrity in healthy people of 72-74 years old. However, the potential roles of ADAMTS18 in central nervous system remain unclear. In this study, we showed that Adamts18 mRNA is highly abundant in developing brains, especially in the cerebellum granular cell layer and the hippocampus dentate gyrus (DG) granular cell layer. Adamts18 knockout (KO) mice displayed higher dendritic branching complexity and spine density on hippocampal DG granular cells. Behavioral tests showed that Adamts18 KO mice had reduced levels of depression-like behaviors compared to their wild-type (WT) littermates. The increased neurite formation could be attributed in part to reduced phosphorylation levels of the collapsin response mediator protein-2 (CRMP2) due to activation of the laminin/PI3K/AKT/GSK-3β signaling pathway. Our findings revealed a critical role of ADAMTS18 in neuronal morphogenesis and emotional control in mice.

The purpose of this study was to evaluate changes in the prevalence and risk factors of cognitive impairment (CI) by analyzing and comparing two cross-sectional epidemiological surveys of CI and its subtypes were performed in a rural area of northern China between 2010 and 2015. Residents aged ≥60 years were drawn in northern China. The Mini Mental State Examination (MMSE) is recommended to test for CI. Dementia was further categorised into Alzheimer's disease (AD), vascular dementia (VaD), and dementia caused by other diseases (ODs). Mild cognitive impairment (MCI) was classified into MCI caused by AD (MCI-A), MCI caused by VaD (MCI-VD), and MCI caused by ODs (MCI-O). The prevalence of CI increased in China. The prevalence of all-cause CI was 30·5% (22.9% MCI and 7.6% dementia) in 2010. The prevalence of all-cause CI was 38.3% (27.8% MCI and 10.5% dementia) in 2015. Similar increases were observed for the prevalence of subtypes of dementia and MCI. These findings suggest an increasing prevalence of CI and its subtypes in China, which may be related to alterations in sociodemographic factors, vascular risk factors and lifestyle changes over time in these cohorts.