Increased Tau Phosphorylation and Tau Truncation, and Decreased Synaptophysin Levels in Mutant BRI2/Tau Transgenic Mice

Abstract

Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease caused by a 10-nucleotide duplication-insertion in the BRI2 gene. FDD is clinically characterized by loss of vision, hearing impairment, cerebellar ataxia and dementia. The main neuropathologic findings in FDD are the deposition of Danish amyloid (ADan) and the presence of neurofibrillary tangles (NFTs). Here we investigated tau accumulation and truncation in double transgenic (Tg-FDD-Tau) mice generated by crossing transgenic mice expressing human Danish mutant BRI2 (Tg-FDD) with mice expressing human 4-repeat mutant Tau-P301S (Tg-Tau). Compared to Tg-Tau mice, we observed a significant enhancement of tau deposition in Tg-FDD-Tau mice. In addition, a significant increase in tau cleaved at aspartic acid (Asp) 421 was observed in Tg-FDD-Tau mice. Tg-FDD-Tau mice also showed a significant decrease in synaptophysin levels, occurring before widespread deposition of fibrillar ADan and tau can be observed. Thus, the presence of soluble ADan/mutant BRI2 can lead to significant changes in tau metabolism and synaptic dysfunction. Our data provide new in vivo insights into the pathogenesis of FDD and the pathogenic pathway(s) by which amyloidogenic peptides, regardless of their primary amino acid sequence, can cause neurodegeneration.

Amyloid and intracellular accumulation of BRI2

“…In FBD, FDD, and Tg-FDD mice, analysis of brain sections shows clusters of swollen neurites surrounding amyloid cores that are recognized by abs specific for the N-terminus of BRI 2 but not by the C-terminal abs (Garringer et al, 2013; Vidal et al, 2009). Since these profiles appeared to be associated with amyloid cores, we analyzed sections from the cerebral cortex, hippocampus, and cerebellum from the cases of sporadic AD (Fig.…”

“…Sections (8-µm thick) were cut and mounted on poly-l-lysine-coated slides and stained with hematoxylin and eosin. Immunohistochemical staining was performed as previously described (Garringer et al, 2013). Immunohistochemical studies were also carried out in paraffin sections from cerebral cortex, hippocampus, and cerebellum from individuals affected by sporadic AD, familial AD (FAD; PSEN1 -V261I mutation; Miravalle et al, 2005), GSS ( PRNP -F198S mutation; Ghetti et al, 1989, 1995), FBD, and FDD (Vidal et al, 1999, 2000), MSTD ( MAPT IVS10 + 3 G > A ; Spillantini et al, 1998), and age-matched controls.…”

“…The NTF is also the subject of additional proteolysis by signal peptide peptidase-like 2 (SPPL2; Fluhrer et al, 2012), releasing an intracellular domain and a BRI 2 C-peptide (Fig. 1; Choi et al, 2004; Garringer et al, 2010, 2013; Martin et al, 2008, 2009). The BRICHOS domain consists of ~ 100 aa and is found in several different type II membrane proteins, including BRI 2 , Chondromodulin-I, CA11, and surfactant protein C (Sanchez-Pulido et al, 2002; Willander et al, 2011).…”

“…The mutant BRI 2 pro-protein is not efficiently processed by PCs to generate m-BRI 2 and has been found to accumulate intracellularly in a transgenic mouse model of FDD (Tg-FDD; Garringer et al, 2013; Tamayev et al, 2010a,b; Vidal et al, 2009). In addition, dystrophic neurites (DNs) consisting of large globular processes surrounding ADan amyloid cores in Tg-FDD mice also show the presence of BRI 2 , in agreement with previous immunohistochemical studies that have shown BRI 2 deposits in DNs of Alzheimer disease (AD), around ischemic lesions, in torpedoes and grumose changes in the cerebellum, as well as in Lewy neurites, ballooned neurons, and neurons undergoing hypoxia (Akiyama et al, 2004; Baron and Pytel, 2016; Del Campo et al, 2014).…”

“…In addition, dystrophic neurites (DNs) consisting of large globular processes surrounding ADan amyloid cores in Tg-FDD mice also show the presence of BRI 2 , in agreement with previous immunohistochemical studies that have shown BRI 2 deposits in DNs of Alzheimer disease (AD), around ischemic lesions, in torpedoes and grumose changes in the cerebellum, as well as in Lewy neurites, ballooned neurons, and neurons undergoing hypoxia (Akiyama et al, 2004; Baron and Pytel, 2016; Del Campo et al, 2014). DNs in Tg-FDD mice are labeled by antibodies (abs) against the N-terminus of BRI 2 but not by abs against the C-terminus of the mutant BRI 2 protein (Garringer et al, 2013), suggesting that they contain m-BRI 2 rather than immature BRI 2 protein.…”