Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-ß (Aß) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aß oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aß oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aß oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated.

Impaired alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and function by mutant huntingtin.

Emerging evidence from studies of Huntington disease (HD) pathophysiology suggests that huntingtin (htt) and its associated protein HAP1 participate in intracellular trafficking and synaptic function. However, it is largely unknown whether AMPA receptor trafficking, which is crucial for controlling the efficacy of synaptic excitation, is affected by the mutant huntingtin with polyglutamine expansion (polyQ-htt). In this study, we found that expressing polyQ-htt in neuronal cultures significantly decreased the amplitude and frequency of AMPAR-mediated miniature excitatory postsynaptic current (mEPSC), while expressing wild-type huntingtin (WT-htt) increased mEPSC. AMPAR-mediated synaptic transmission was also impaired in a transgenic mouse model of HD expressing polyQ-htt. The effect of polyQ-htt on mEPSC was mimicked by knockdown of HAP1 and occluded by the dominant negative HAP1. Moreover, we found that huntingtin affected mESPC via a mechanism depending on the kinesin motor protein, KIF5, which controls the transport of GluR2-containing AMPARs along microtubules in dendrites. The GluR2/KIF5/HAP1 complex was disrupted and dissociated from microtubules in the HD mouse model. Together, these data suggest that AMPAR trafficking and function is impaired by mutant huntingtin, presumably due to the interference of KIF5-mediated microtubule-based transport of AMPA receptors. The diminished strength of glutamatergic transmission could contribute to the deficits in movement control and cognitive processes in HD conditions.

Phosphatidylinositol (4,5)-bisphosphate regulation of N-methyl-D-aspartate receptor channels in cortical neurons.

The membrane phospholipid phosphatidylinositol (4,5)-bisphosphate (PIP(2)) has been implicated in the regulation of several ion channels and transporters. In this study, we examined the impact of PIP(2) on N-methyl-D-aspartate receptors (NMDARs) in cortical neurons. Blocking PIP(2) synthesis by inhibiting phosphoinositide-4 kinase, or stimulating PIP(2) hydrolysis via activation of phospholipase C (PLC), or blocking PIP(2) function with an antibody caused a significant reduction of NMDAR-mediated currents. On the other hand, inhibition of PLC or application of PIP(2) caused an enhancement of NMDAR currents. These electrophysiological effects were accompanied by changes in NMDAR surface clusters induced by agents that manipulate PIP(2) levels. The PIP(2) regulation of NMDAR currents was abolished by the dynamin inhibitory peptide, which blocks receptor internalization. Agents perturbing actin stability prevented PIP(2) regulation of NMDAR currents, suggesting the actin-dependence of this effect of PIP(2). Cofilin, a major actin depolymerizing factor, which has a common binding sequence for actin and PIP(2), was required for PIP(2) regulation of NMDAR currents. It is noteworthy that the PIP(2) regulation of NMDAR channels was impaired in a transgenic mouse model of Alzheimer's disease, probably because of the amyloid-beta disruption of PIP(2) metabolism. Taken together, our data suggest that continuous synthesis of PIP(2) at the membrane might be important for the maintenance of NMDARs at the cell surface. When PIP(2) is lost, cofilin is released from the PIP(2) complex and is rendered free to depolymerize actin. With the actin cytoskeleton no longer intact, NMDARs are internalized via a dynamin/clathrin-dependent mechanism, leading to reduced NMDAR currents.