Discoveries in Neuroscience

A genetic link between Alzheimer's disease and inflammation

Two independent research teams identified a heterozygous rare variant in TREM2 (Triggering receptor expressed on myeloid cells 2) associated with a significant increase in the risk for lateonset Alzheimer's disease. The mutation is expressed as a R47H substitution in the extracellular immunoglobulin-like domain of the molecule. In both studies, the investigators build on nextgeneration genome and exome sequencing methodologies to develop a catalog of low-frequency variants that were likely to affect protein function, and test them in multiple case-control Alzheimer's datasets using a combination of genotyping and imputation (genotypic inference of untyped markers). Although this variant occurs in the population at a significant lower frequency than the ApoE e4 allele, it confers risk with an effect size that is similar to that of ApoE e4 (ORs in the 3.0 – 4.5 range). Further, non-Alzheimer's elderly carriers of the mutation have poorer cognitive function when compared to non-carriers. TREM2 is a member of the immunoglobulin super-family and functions as an innate immune receptor recognizing anionic lipopolysaccharides in the cell wall of bacteria. TREM2 is expressed in myeloid cells, including osteoclasts, macrophages and microglia. Interestingly, homozygous loss of function in TREM2 has been linked to Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), a disorder affecting bones and brain with progressive presenile inflammatory neurodegeneration. Thus, the same gene plays a significant role in two diseases previously considered unrelated, one that is severe and has an early onset caused by homozygous loss of function and the other that has a late onset and is caused by a heterozygous loss of function variant. The authors in both papers speculate that reduced TREM2 activity affect beta amyloid and cellular debris clearance and/or perpetuates damaging inflammatory responses in the brain (N Engl J Med 2013, 368:107-116, 117-127).

Not just plumbing in the brain: the vasculome

The complex network of brain blood vessels may not just be empty pipes for blood flow. This so-called “brain vasculome” may actually be an active organ that communicates with the brain itself. In this study, the investigators mapped the brain vasculome of the mouse brain. Using endothelial cells purified from mouse brain, heart and kidney glomeruli, they extracted and profiled RNA for gene expression analysis. They show that the brain vasculome is unique and different from vasculomes in heart and kidney. They also show that the brain vasculome contains many active signaling networks, such as functionally active networks including cell adhesion, transporter activity, plasma membrane, leukocyte transmigration, Wnt signaling pathways and those involved in angiogenesis. Perhaps most importantly, they show that the brain vasculome is linked with GWAS-identified genes for stroke, Alzheimer's disease and Parkinson's disease. When they compared the mouse brain vasculome with human databases for representative plasma proteins there was significant overlap suggesting that the vasculome may be an important source of circulating proteins that could serve as biomarkers for diseases. Since the endothelial surface is by far the single largest organ in contact with blood, the brain vasculome can be a new database for biomarker mining. The implications for understanding and identifying mechanisms and disease targets for neurovascular disease are truly vast (Plos one 2012, 7:e52665).

Angiogenesis and axonal remodeling in EAE

Using the MBP-induced experimental autoimmune encephalitis (EAE) model in SJL/J mice, Muramatsu and colleagues report the development of new blood vessels around inflammatory lesions in the spinal cord, followed by the sprouting of adjacent corticospinal tract fibers, formation of compensatory circuits, and significant recovery of motor function in the affected animals. In vitro-culturing of neurons and vessels and analysis of the culture supernatants lead to the discovery of prostacyclin as a key mediator of this phenomena. The molecular inhibition of prostacyclin receptor signaling with siRNAS impaired motor recovery, whereas the prostacyclin receptor agonist Iloprost promoted axonal remodeling and motor recovery after the induction of EAE. On the other hand, treatment with Iloprost does not reduce the clinical onset of EAE, suggesting that the receptor is not involved in the development of EAE and prostacyclin and its receptor do not have a major role in regulating inflammation in EAE. Thus, the findings show that prostacyclin (and perhaps other soluble factors) released from the inflammationinduced neovascular endothelium promote axonal rewiring and is a promising molecule to promote functional recovery in neurodegenerative diseases (Nature Med 2012, 18:1658-1664).