Significance Communication between nerve cells occurs at specialized cellular structures known as synapses. Loss of synaptic function is associated with cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here we describe a pathway for synaptic damage whereby amyloid-β 1–42 peptide (Aβ 1–42 ) releases, via stimulation of α7 nicotinic receptors, excessive amounts of glutamate from astrocytes, in turn activating extrasynaptic NMDA-type glutamate receptors (eNMDARs) to mediate synaptic damage. The Food and Drug Administration-approved drug memantine offers some beneficial effect, but the improved eNMDAR antagonist NitroMemantine completely ameliorates Aβ-induced synaptic loss, providing hope for disease-modifying intervention in AD.

Emerging evidence suggests that myocyte enhancer factor 2 (MEF2) transcription factors act as effectors of neurogenesis in the brain, with MEF2C the predominant isoform in developing cerebrocortex. Here, we show that conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size. NSC proliferation and survival were not affected. Conditional null mice surviving to adulthood manifested more immature electrophysiological network properties and severe behavioral deficits reminiscent of Rett syndrome, an autism-related disorder. Our data support a crucial role for MEF2C in programming early neuronal differentiation and proper distribution within the layers of the neocortex.neurogenesis ͉ synaptogenesis ͉ autism ͉ Rett syndrome K nockdown of the transcription factor MEF2C in mature cerebrocortical neurons results in increased synaptic number and activity (1). To facilitate analysis of MEF2C function in early neuronal development, we engineered a conditional knockout in NSCs by crossing floxed Mef2c mice with Nestin-Cre mice. In contrast to the findings in more mature neurons, we found a striking alteration in the distribution of new neurons in the neocortex and the opposite effect on synaptic activity, i.e., decreased neurotransmission persisting into adulthood.MEF2C belongs to the myocyte enhancer factor 2 (MEF2) subfamily of the MADS (MCM1-agamous-deficiens-serum response factor) gene family (2, 3). We cloned MEF2C from developing mouse brain, and Eric Olson and colleagues then discovered it in the heart (2, 4, 5). In cerebrocortex, MEF2 transcriptional activity is restricted to differentiated cortical neurons in a specific laminar pattern, and its distribution increases along the rostrocaudal axis (2, 4, 6). These features led to speculation on the potential role of MEF2C in the architechtonics of the cerebral cortex (2). Previous studies demonstrated an important role for MEF2C in heart development (7). In the CNS, MEF2C is involved in neuronal apoptosis (8) and synapse formation (1, 9) in vitro or in brain slices. Most recently, our laboratory discovered that a constitutively active form of MEF2C induces embryonic stem cells to commit to a neuronal fate in a virtually exclusive fashion (10). However, studies on the effect of endogenous MEF2C on CNS neurons in vivo were impeded by the embryonic lethality of conventional Mef2c-null mice because of cardiovascular defects at embryonic day (E) 9.5, before brain development (7). Here, we report that conditionally knocking out the Mef2c gene in neural progenitors causes abnormal aggregation and compaction of neurons migrating into the lower layers of the neocortex during development. Knockout mice surviving to adulthood manifest smaller, apparently less mature neurons and smaller whole brain size, with resultant aberrant electrophysiology and behavior.

Impaired adult neurogenesis has been observed in several neurodegenerative diseases, including human immunodeficiency virus (HIV-1)-associated dementia (HAD). Here we report that the HIV-envelope glycoprotein gp120, which is associated with HAD pathogenesis, inhibits proliferation of adult neural progenitor cells (aNPCs) in vitro and in vivo in the dentate gyrus of the hippocampus of HIV/gp120-transgenic mice. We demonstrate that HIV/gp120 arrests cell-cycle progression of aNPCs at the G1 phase via a cascade consisting of p38 mitogen-activated protein kinase (MAPK) --> MAPK-activated protein kinase 2 (a cell-cycle checkpoint kinase) --> Cdc25B/C. Our findings define a molecular mechanism that compromises adult neurogenesis in this neurodegenerative disorder.

Objective Prolonged human immunodeficiency virus-1 (HIV-1) infection leads to neurological debilitation, including motor dysfunction and frank dementia. Although pharmacological control of HIV infection is now possible, HIV-associated neurocognitive disorders (HAND) remain intractable. Here, we report that chronic treatment with erythropoietin (EPO) and insulin-like growth factor-I (IGF-I) protects against HIV/gp120-mediated neuronal damage in culture and in vivo. Methods Initially, we tested the neuroprotective effects of various concentrations of EPO, IGF-I, or EPO+IGF-I from gp120-induced damage in vitro. To assess the chronic effects of EPO+IGF-I administration in vivo, we treated HIV/gp120-transgenic or wild-type mice transnasally once a week for 4 months and subsequently conducted immunohistochemical analyses. Results Low concentrations of EPO+IGF-I provided neuroprotection from gp120 in vitro in a synergistic fashion. In vivo, EPO+IGF-I treatment prevented gp120-mediated neuronal loss, but did not alter microgliosis or astrocytosis. Strikingly, in the brains of both humans with HAND and gp120-transgenic mice, we found evidence for hyperphosphorylated tau protein (paired helical filament-I tau), which has been associated with neuronal damage and loss. In the mouse brain following transnasal treatment with EPO+IGF-I, in addition to neuroprotection we observed increased phosphorylation/activation of Akt (protein kinase B) and increased phosphorylation/inhibition of glycogen synthase kinase (GSK)-3β, dramatically decreasing downstream hyperphosphorylation of tau. These results indicate that the peptides affected their cognate signaling pathways within the brain parenchyma. Interpretation Our findings suggest that chronic combination therapy with EPO+IGF-I provides neuroprotection in a mouse model of HAND, in part, through cooperative activation of phosphatidylinositol 3-kinase/Akt/GSK-3β signaling. This combination peptide therapy should therefore be tested in humans with HAND.

Thus, Insulin115 exhibits a unique in vivo and in vitro profile and thereby represents an excellent candidate for a once-weekly insulin analogue.

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HIV-associated neurocognitive disorder (HAND) consists of motor and cognitive dysfunction in a relatively large percentage of patients with AIDS. Prior work has suggested that at least part of the neuronal and synaptic damage observed in HAND may occur due to excessive stimulation of NMDA-type glutamate receptors (NMDARs). Here, we compared pharmacological and genetic manipulation of NMDAR activity using an improved derivative of the NMDAR antagonist memantine, termed NitroMemantine, and the modulatory NMDAR subunit GluN3A in the HIV/gp120 transgenic (tg) mouse model of HAND. Interestingly, we found that while both NitroMemantine and GluN3A have been shown to inhibit NMDAR activity, NitroMemantine protected synapses in gp120 tg mice, but overexpression of GluN3A augmented the damage. Given recent findings in the field, one explanation for this apparently paradoxical result is the location of the NMDARs primarily affected, with NitroMemantine inhibiting predominantly extrasynaptic pathologically-activated NMDARs, but GluN3A disrupting normal NMDAR-mediated neuroprotective activity via inhibition of synaptic NMDARs.

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