Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that can regulate microtubule assembly in neurons. This function of CRMP2 is regulated by phosphorylation by glycogen synthase kinase 3 (GSK3) and cyclin-dependent kinase 5 (Cdk5). Here, using novel phosphospecific antibodies, we demonstrate that phosphorylation of CRMP2 at Ser522 (Cdk5-mediated) is increased in Alzheimer's disease (AD) brain, while CRMP2 expression and phosphorylation of the closely related isoform CRMP4 are not altered. In addition, CRMP2 phosphorylation at the Cdk5 and GSK3 sites is increased in cortex and hippocampus of the triple transgenic mouse [presenilin-1 (PS1) M146V KI; Thy1.2-amyloid precursor protein (APP) swe ; Thy1.2tau P301L ] that develops AD-like plaques and tangles, as well as the double (PS1 M146V KI; Thy1.2-APP swe ) transgenic mouse. The hyperphosphorylation is similar in magnitude to that in human AD and is evident by 2 months of age, ahead of plaque or tangle formation. Meanwhile, there is no change in CRMP2 phosphorylation in two other transgenic mouse lines that display elevated amyloid b peptide levels (Tg2576 and APP/amyloid b-binding alcohol dehydrogenase). Similarly, CRMP2 phosphorylation is normal in hippocampus and cortex of Tau(P301L) mice that develop tangles but not plaques. These observations implicate hyperphosphorylation of CRMP2 as an early event in the development of AD and suggest that it can be induced by a severe APP over-expression and/or processing defect. Keywords: Alzheimer's disease, collapsin response mediator protein 2, cyclin-dependent kinase 5, glycogen synthase kinase 3, phosphorylation.

The Tg2576 transgenic mouse is an extensively characterized animal model for Alzheimer's disease (AD). Similar to AD, these mice suffer from progressive decline in several forms of declarative memory including contextual fear conditioning and novel object recognition (NOR). Recent work on this and other AD animal models suggests that initial cognitive deficits are due to synaptic dysfunction that, with the correct intervention, are fully treatable. We recently reported that acute calcineurin (CaN) inhibition with FK506 ameliorates one form of declarative memory (contextual fear conditioning) impairment in 5 months old Tg2576.This study tested whether acute CaN inhibition rescues deficits in an additional form of declarative memory, spontaneous object recognition, by employing the NOR paradigm. Furthermore, we determined whether FK506 rescue of NOR deficits depends on the retention interval employed and therefore is restricted to short-term, intermediate-term, or long-term memory (STM, ITM or LTM, respectively). In object recognition, Tg2576 are unimpaired when NOR is tested as a STM task and CaN inhibition with FK506 does not influence NOR STM performance in Tg2576 or WT mice. Tg2576 were impaired in NOR compared to WT mice when a 4 or 24 hour retention interval was employed to model ITM and LTM, respectively. Acute CaN inhibition prior to and during the training session reversed these deficits in Tg2576 mice with no effect on WT performance. Our findings demonstrate that aberrant CaN activity mediates object recognition deficits in 5 months old Tg2576 when NOR is employed as a test for ITM and LTM. In human AD, CaN inhibition may lead the way for therapeutics to improve declarative memory performance as demonstrated in a mouse model for AD.

Misfolded amyloid beta peptide (Aβ) is a pathological hallmark of Alzheimer's disease (AD), a neurodegenerative illness characterized by cognitive deficits and neuronal loss. Transgenic mouse models of Aβ over-production indicate that Aβ-induced cognitive deficits occur in the absence of overt neuronal death, suggesting that while extensive neuronal death may be associated with later stages of the human disease, subtle physiological changes may underlie initial cognitive deficits. Therefore, identifying signaling elements involved in those Aβ-induced cognitive impairments that occur prior to loss of neurons may reveal new potential pharmacological targets. Here we report that the enzymatic activity of calcineurin, a key protein phosphatase involved in phosphorylationdependent kinase activity crucial for synaptic plasticity and memory function, is up-regulated in the CNS of the Tg2576 animal model for Aβ over production. Furthermore, acute treatment of Tg2576 mice with the calcineurin inhibitor FK506 (10 mg/kg ip) improves memory function. These results indicate that calcineurin may mediate some of the cognitive effects of excess Aβ such that inhibition of calcineurin shall be further explored as a potential treatment to reverse cognitive impairments in AD.

Vision is dependent on ordered neuronal representations or maps of visual space. These maps depend on precise connections between retinal axons and their targets cells. In mammals, nerve fibres from right and left eyes produce congruent maps of contralateral visual space in adjacent layers of the lateral geniculate nucleus (LGN). We have identified an autosomal recessive mutation in Belgian sheepdogs that eliminates the optic chiasm. In these mutants, all retinal axons project into the ipsilateral optic tract, including those originating in the nasal hemiretina that normally cross midline. These animals exhibit a pronounced horizontal nystagmus. The abnormal ipsilaterally directed nasal fibres innervate the LGN as if they had successfully crossed the midline, terminating in the appropriate layer of the nucleus. As a consequence, the LGN contains non-congruent, mirror-image maps of visual space in adjacent layers. These results show that there is a robust affinity between nasal and temporal retinal axons and specific LGN layers even when all retinal axons originate from a single eye.

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