Alzheimer's disease (AD) is characterized by progressive cognitive decline and the presence of aggregates of amyloid beta (plaques) and hyperphosphorylated tau (tangles). Early diagnosis through neuropsychological testing is difficult due to comorbidity of symptoms between AD and other types of dementia. As a result, there is a need to identify the range of behavioral phenotypes expressed in AD. In the present study, we utilized a transgenic rat (TgF344-AD) model that bears the mutated amyloid precursor protein as well as presenilin-1 genes, resulting in progressive plaque and tangle pathogenesis throughout the cortex. We tested young adult male and female TgF344-AD rats in a spatial memory task in the Morris water maze and for anxiety-like behavior in the elevated plus-maze. Results indicated that regardless of sex, TgF344-AD rats exhibited increased anxiety-like behavior in the elevated plus-maze, which occurred without significant deficits in the spatial memory. Together, these results indicate that enhanced anxiety-like behavior represents an early-stage behavioral marker in the TgF344-AD rat model.

Spatial navigation is impaired in early stages of Alzheimer’s disease, and may be a defining behavioral marker of preclinical AD. A new rat model (TgF344-AD) of AD overcomes many limitations of other rodent models, though spatial navigation has not been comprehensively assessed. Using the hidden and cued platform variants of the Morris water task, a longitudinal assessment of spatial navigation was conducted on TgF344-AD (n = 16) and Fischer 344 (n = 12) male and female rats at three age ranges: 4 to 5 months, 7 to 8, and 10 to 11 months of age. TgF344-AD rats exhibited largely intact navigation at 4–5 months, with deficits in the hidden platform task emerging at 7–8 months and becoming significantly pronounced at 10–11 months of age. In general, TgF344-AD rats displayed less accurate swim trajectories to the platform and searched a wider area around the platform region compared to wildtype rats. Impaired navigation occurred in the absence of deficits in acquiring the procedural task demands or navigation to the cued platform location. Together, the results indicate that TgF344-AD rats exhibit comparable navigational deficits to those found in individuals with preclinical-AD.

6 7 8 Abstract 24Spatial navigation is impaired in early stages of Alzheimer's disease (AD), and 25 may be a defining behavioral marker of preclinical AD. Nevertheless, limitations of 26 diagnostic criteria for AD and within animal models of AD make characterization of 27 preclinical AD difficult. A new rat model (TgF344-AD) of AD overcomes many of these 28 limitations, though spatial navigation has not been comprehensively assessed. Using the 29 hidden and cued platform variants of the Morris water task, a longitudinal assessment of 30 spatial navigation was conducted on TgF344-AD (n=16) and Fischer 344 (n=12) male 31 and female rats at three age ranges: 4 to 5 months, 7 to 8, and 10 to 11 months of age. 32TgF344-AD rats exhibited largely intact navigation at 4-5 and 7-8 months of age, with 33 deficits in the hidden platform task emerging at 10-11 months of age. In general, TgF344-34 AD rats displayed less accurate swim trajectories to the platform and a wider search area 35 around the platform region compared to wildtype rats. Impaired navigation occurred in 36 the absence of deficits in acquiring the procedural task demands or navigation to the cued 37 platform location. Together, the results indicate that TgF344-AD rats exhibit comparable 38 deficits to those found in individuals in the early stages of AD. 39 40 41 42 43 44 45 46 47Alzheimer's disease (AD) is the most common form of dementia in the United 48 States and is characterized by progressive cognitive decline and neurodegeneration 49 (Association and others, 2017). AD pathology, marked by amyloid plaques and 50 neurofibrillary tangles that accumulate throughout the limbic system and hippocampus, is 51 predicted to initiate up to 20 years prior to the onset of behavioral symptoms (Gao et al., 52 1998; Mielke et al., 2014). Although the long preclinical period poses a significant 53 challenge to early diagnosis of AD (Dubois et al., 2016; Graham et al., 2017) subtle 54 changes in memory, as observed in amnestic mild cognitive impairment (aMCI), can 55 indicate an increased risk of progressing to dementia (Petersen, 2004; Winblad et al., 56 2004). However, because not all cases of aMCI progress to AD, there is a growing need 57 for sensitive behavioral assessments for AD diagnosis. 58Mounting evidence suggests that spatial disorientation, sometimes referred to as 59 wandering, are among the earliest memory complaints in AD (Bianchini et al., 2014; Bird 60 et al., 2010; Chan et al., 2016; Guariglia and Nitrini, 2009; Pai and Jacobs, 2004; Yew et 61 al., 2013). In general, disorientation is characterized as deficient localization of hidden 62 goals (Hort et al., 2007), a loss of direction sense (Cushman et al., 2008; deIpolyi et al., 63 2007; Monacelli et al., 2003; Tu et al., 2015), or an impairment in correctly identifying 64 familiar spatial scenes after a small change in view-point (Bird et al., 2010; Chan et al., 65 2016). Deficits in establishing or utilizing map-like (allocentric) frameworks for 66 navigation ...

Hedgehog proteins are embryonic induction factors that play a role in the development of the central and peripheral nervous systems. The Hedgehog proteins and their signaling pathway continue to be expressed in the adult nervous system, where their role is not known. In adult peripheral nerve, Sonic Hedgehog (Shh) is expressed in a subset of motor neurons, Desert Hedgehog (Dhh) is expressed in Schwann cells, and the Hedgehog receptor Patched (Ptc) and the Hedgehog‐responsive transcription factor Gli are expressed predominantly in perineurial cells. We have used the mouse sciatic nerve crush model to assess whether the Hedgehog pathway plays a role in nerve regeneration. The sciatic nerve was crushed in adult, male CD‐1 mice, and the expression of Dhh, Ptc‐1, Ptc‐2 and Gli‐1 was examined 1, 3, 7 and 13 days later. The ability of exogenous and endogenous Hedgehog proteins to influence functional recovery after nerve crush was assessed by measuring toe spread and ability to grip with the hindpaws. Little change in expression was seen 1 or 3 days after nerve crush. At 7 days and, to a greater extent, 13 days, there was a pronounced increase in expression of Dhh in Schwann cells and Ptc‐1 in perineurial cells. Expression of Ptc‐2 and Gli‐1 increased not only in the perineurial layer, but also in the endoneurium. Treatment with a Shh‐Ig fusion protein (1 mg/kg s.c. every other day) improved recovery of both toe spread and ability to grip. Conversely, treatment with an anti‐Hedgehog neutralizing antibody (10 mg/kg s.c. every other day) slowed functional recovery, while an isotype control antibody had no effect. These findings suggest that endogenous Hedgehog proteins play a role in promoting regeneration following nerve injury and that administration of exogenous Hedgehog proteins can further accelerate recovery of injured peripheral nerves. Therefore, Hedgehog proteins may be useful in the treatment of nerve injury and peripheral neuropathies.