Classical laboratory strains show limited genetic diversity and do not harness natural genetic variation. Mouse models relevant to Alzheimer’s disease (AD) have largely been developed using these classical laboratory strains, such as C57BL/6J (B6), and this has likely contributed to the failure of translation of findings from mice to the clinic. Therefore, here we test the potential for natural genetic variation to enhance the translatability of AD mouse models. Two widely used AD-relevant transgenes, APP swe and PS1 de9 ( APP/PS1 ), were backcrossed from B6 to three wild-derived strains CAST/EiJ, WSB/EiJ, PWK/PhJ, representative of three Mus musculus subspecies. These new AD strains were characterized using metabolic, functional, neuropathological and transcriptional assays. Strain-, sex- and genotype-specific differences were observed in cognitive ability, neurodegeneration, plaque load, cerebrovascular health and cerebral amyloid angiopathy. Analyses of brain transcriptional data showed strain was the greatest driver of variation. We identified significant variation in myeloid cell numbers in wild type mice of different strains as well as significant differences in plaque-associated myeloid responses in APP/PS1 mice between the strains. Collectively, these data support the use of wild-derived strains to better model the complexity of human AD.

Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

The survival of juvenile Chinook Salmon through the lower San Joaquin River and Sacramento–San Joaquin River Delta in California was estimated using acoustic tags in the spring of 2009 and 2010. The focus was on route use and survival within two major routes through the Delta: the San Joaquin River, which skirts most of the interior Delta to the east, and the Old River, a distributary of the San Joaquin River leading to federal and state water export facilities that pump water out of the Delta. The estimated probability of using the Old River route was 0.47 in both 2009 and 2010. Survival through the southern (i.e., upstream) portion of the Delta was very low in 2009, estimated at 0.06, and there was no significant difference between the Old River and San Joaquin River routes. Estimated survival through the Southern Delta was considerably higher in 2010 (0.56), being higher in the Old River route than in the San Joaquin route. Total estimated survival through the entire Delta (estimated only in 2010) was low (0.05); again, survival was higher through the Old River. Most fish in the Old River that survived to the end of the Delta had been salvaged from the federal water export facility on the Old River and trucked around the remainder of the Delta. The very low survival estimates reported here are considerably lower than observed salmon survival through comparable reaches of other large West Coast river systems and are unlikely to be sustainable for this salmon population. More research into mortality factors in the Delta and new management actions will be necessary to recover this population.Received March 28, 2012; accepted September 5, 2012

Survival of juvenile fall‐run Chinook Salmon Oncorhynchus tshawytscha through the San Joaquin River Delta of California (hereafter, “Delta”) has been low for most estimates since 2002 and has been consistently low since 2010. From 2010 through 2015, annual estimates of the probability of surviving through the Delta (from Mossdale to Chipps Island, approximately 92 river kilometers) ranged from 0 to 0.05, based on acoustic‐telemetry data from smolt‐sized hatchery Chinook Salmon. River conditions were poor in most of these years; average daily river discharge into the Delta from the San Joaquin River was <40 m3/s in four of the six study years. In the high flow year of 2011 (average daily river discharge = 278–308 m3/s), the juvenile survival probability through the Delta was estimated at only 0.02 (SE < 0.01), suggesting increased flows alone will not be sufficient to resolve the low survival through the Delta. The low survival in this short portion of the salmon's life history makes achieving a minimal smolt‐to‐adult ratio of ≥2% nearly impossible for this fish stock. Over half of the fish surviving through the Delta during 6 years of study were salvaged at the Central Valley Project's water export facility and transported for release just upstream of Chipps Island.