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-β (Aβ) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aβ 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 Aβ oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aβ 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. memory dysfunction | neural plasticity | aging | T-maze | hippocampus A lzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of abnormally processed proteins in neurofibrillary tangles (NFTs) and senile plaques (1). These lesions are present in both familial and sporadic forms of AD. Familial AD is linked to inherited mutations in AD-related genes and represents a small percentage of AD cases, whereas sporadic AD represents the vast majority of cases and is not inherited. Results from transgenic mice bearing mutations in APP, PSEN1/2, and TAU show synaptic dysfunction in early stages of AD, before overt neurodegeneration (2, 3). More recent studies have demonstrated a critical role for soluble Aβ oligomers as an early trigger for AD, as well as associations with memory and neural plasticity loss (4-8).Although transgenic mice have been extremely useful in elucidating the pathological mechanisms of AD, they have some substantial limitations. Examples include the absence of tau mutations linked to AD except for a triple transgenic mouse 3xTg-AD, bearing mutations for APP, PSEN1/2, and TAU (9); inability to develop the whole spectrum of the disease; overexpression of transgenes into a nonphysiological scenario; and the fact that the manipulated genes represent only familial, not sporadic forms of AD (10, 11). It would be highly desirable to have a nontransgenic model of AD to complement the existing models. Several species naturally develop features of AD with age; however, the usefulness of these species is limited, because none exhibits the full spectrum of AD-related alterations (12-14). For example, the Aβ peptide sequences of Cavia porcellus (guinea pig) and Microcebus murinus are similar to that of huma...

Background:It is important to understand the pathophysiology of Huntington disease (HD). Results: Huntingtin altered AMPAR-mediated synaptic transmission via a mechanism depending on the microtubule (MT) motor KIF5. The AMPAR/KIF5/MT complex was disrupted in a HD mouse model. Conclusion: AMPAR trafficking and function is impaired by mutant huntingtin. Significance: It could underlie the deficits in movement control and cognitive processes in HD conditions.

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-␤ 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/clathrindependent mechanism, leading to reduced NMDAR currents.The N-methyl-D-aspartate receptor (NMDAR), one of the major glutamate receptor channels in central neurons, plays a key role in multiple neuronal functions, including synapse formation, synaptic plasticity, learning, and memory. Dysregulation of NMDARs has been implicated in ischemia, epilepsy, and neuropsychiatric disorders (Dingledine et al., 1999;Lau and Zukin, 2007). Synaptic targeting and incorporation of NMDA receptors are dynamically regulated (Wenthold et al., 2003). After being released from the endoplasmic reticulum, NMDARs are rapidly transported along microtubule tracks in dendritic shafts (Washbourne et al., 2002;Yuen et al., 2005), followed by being delivered to actinrich dendritic spines. NMDARs are tethered to actin cytoskeleton via scaffolding and adaptor proteins, such as ␣-actinin and postsynaptic density-95 (Wyszynski et al., 1997;Pak et al., 2001). Several mechanisms have been proposed to be important for stabilizing and/or promoting surface NMDA receptor expression, including the PDZ domain-mediated interactions between NR2 subunits and postsynaptic density-95 (Kornau et al., 1995;Roche et al., 2001;Lin et al., 2004) and tyrosine dephosphorylation of NR2 subunits that triggers clathrin-dependent endocytosis (Vissel et al., 2001;Prybylowski et al., ...