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Loss of memory is an inevitable clinic sign in aging, but its underlying mechanisms remain unclear. Here we show that death-associated protein kinase (DAPK1) is involved in the decays of learning and memory in aging via degradation of Caytaxin, a brain-specific member of BNIP-2. DAPK1 becomes activated in the hippocampus of mice during aging. Activation of DAPK1 is closely associated with degradation of Caytaxin protein. Silencing Caytaxin by the expression of small interfering RNA (siRNA) that targets specifically to Caytaxin in the hippocampus of adult mice impairs the learning and memory. Genetic inactivation of DAPK1 by deletion of DAPK1 kinase domain prevents the degradation of Caytaxin and protects against learning and memory declines. Thus, activation of DAPK1 impairs learning and memory by degrading Caytaxin during aging.

Aggregation of amyloid-β (Aβ) peptides, which are the cleavage products of amyloid precursor protein (APP), is a major pathological hallmark in the brain of Alzheimer's disease (AD). Now, we know little about the roles of APP translation in the disease progression of AD. Here, we show that BC1, a long noncoding RNA (lncRNA), is expressed in the brain of AD mice. BC1 induces APP mRNA translation via association with a fragile X syndrome protein (FMRP). Inhibition of BC1 or BC1-FMRP association in AD mice blocks aggregation of Aβ in the brain and protects against the spatial learning and memory deficits. Expression of exogenous BC1 in excitatory pyramidal neurons of mice induces Aβ peptides accumulation and the spatial learning and memory impairments. This study provides a novel mechanism underlying aggregation of Aβ peptides via BC1 induction of APP mRNA translation and hence warrants a promising target for AD therapy.

Immediately following ischemia, glutamate accumulates in the extracellular space and results in extensive stimulation of its receptors including N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. A large amount of Ca2+ influx directly through the receptor-gated ion channels which leads to Ca2+ overload and triggers several downstream lethal reactions. As a result, cell dies via apoptosis or necrosis, or both. Death-associated protein kinase 1 (DAPK1) physically and functionally interacts with the NMDA receptor GluN2B subunit at extra-synaptic sites and this interaction acts as a central mediator for stroke damage. The goal of this study is to explore an effective strategy in the treatment of stroke with a molecular genetic manipulation to interrupt DAPK1-GluN2B interaction. We generated a mutant strain of mice with the conditional deletion of GluN2B C-terminal tail consisting of amino acids 886-1269 in the forebrain excitatory neurons (the GluN2B mutant mice) and tested the protective effects of this mutation in stroke damages. GluN2B mutation effectively disrupted the DAPK1-GluN2B interaction and inhibited extra-synaptic NMDA receptor currents without affecting synaptic NMDA receptor channel activity in the central neurons. GluN2B mutation protected against stroke damages both in vitro and in vivo and hence improved behavioral performance. Disruption of the DAPK1-GluN2B interaction is therapeutically effective against stroke damages.

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin (CaM)-dependent serine/threonine protein kinase, plays important roles in diverse apoptosis pathways not only in tumor suppression but also in neuronal cell death. The requirement of DAPK1 catalytic activity for its proposed cell functions and the elevation of catalytic activity of DAPK1 in injured neurons in models of neurological diseases, such as ischemia and epilepsy, validate that DAPK1 can be taken as a potential therapeutic target in these diseases. Recent studies show that DAPK1-NR2B, DAPK1-DANGER, DAPK1-p53, and DAPK1-Tau are currently known pathways in stroke-induced cell death, and blocking these cascades in an acute treatment effectively reduces neuronal loss. In this review, we focus on the role of DAPK1 in neuronal cell death after stroke. We hope to provide exhaustive summaries of relevant studies on DAPK1 signals involved in stroke damage. Therefore, disrupting DAPK1-relevant cell death pathway could be considered as a promising therapeutic approach in stroke.

Olfactory dysfunction is recognized as a potential risk factor for Alzheimer's disease (AD). We have reported previously that olfactory deprivation by olfactory bulbectomy (OBX) induced Alzheimer's-like pathological changes and behavioral abnormalities. However, the acute OBX model undergoes surgical-induced brain parenchyma loss and unexpected massive hemorrhage so that it cannot fully mimic the progressive olfactory loss and neurodegeneration in AD. Here, we employed the mice loss of cyclic nucleotide-gated channel alpha 2 (Cnga2) which is critical for olfactory sensory transduction, to investigate the role of olfactory dysfunction in AD pathological process. We found that impaired learning and memory abilities, loss of dendrite spines, as well as decrement of synaptic proteins were displayed in Cnga2 knockout mice. Moreover, Aβ overproduction, tau hyperphosphorylation, and somatodendritic translocation were also found in Cnga2 knockout mice. Our findings suggest that progressive olfactory loss leads to Alzheimer's-like behavior abnormities and pathological changes.

Endothelin1 (ET1) is a potent vasoconstrictor that is also known to be a neuropeptide that is involved in neural circuits. We examined the role of ET1 that has been implicated in the anxiogenic process. We found that infusing ET1 into the IL cortex increased anxiety-like behaviors. The ET(A) receptor (ET(A)R) antagonist (BQ123) but not the ET(B) receptor (ET(B)R) antagonist (BQ788) alleviated ET1-induced anxiety. ET1 had no effect on GABAergic neurotransmission or NMDA receptor (NMDAR)-mediated neurotransmission, but increased AMPA receptor (AMPAR)-mediated excitatory synaptic transmission. The changes in AMPAR-mediated excitatory postsynaptic currents were due to presynaptic mechanisms. Finally, we found that the AMPAR antagonists (CNQX) and BQ123 reversed ET1's anxiogenic effect, with parallel and corresponding electrophysiological changes. Moreover, infusing CNQX + BQ123 into the IL had no additional anxiolytic effect compared to CNQX treatment alone. Altogether, our findings establish a previously unknown anxiogenic action of ET1 in the IL cortex. AMPAR-mediated glutamatergic neurotransmission may underlie the mechanism of ET1-ET(A)R signaling pathway in the regulation of anxiety.

Cognition in all mammals including human beings declines during aging. The cellular events responsible for this decay involve a reduction of neurogenesis in the dentate gyrus. Here, we show that treatment with a nature product from a traditional Chinese medicine, namely salidroside restores the capacity of the dentate gyrus to generate new neurons and intercepts learning and memory decays in mice during aging. We uncover that new neurons in aging mice have functional features of an adult granule neuron by forming excitatory synapses with their putative targeting neurons. Genetic inhibition of synaptic transmission from new neurons abolishes the therapeutic effects of salidroside in behavioral tests. We also identify that salidroside targets CREB transcription for the survival of new neurons in the dentate gyrus of old mice. Thus, salidroside is therapeutically effective against learning and memory decays via stimulation of CREB-dependent functional neurogenesis in aging.

Cholinergic system is very important for many higher brain functions, including learning and memory. Cholinergic neurons, especially those in the basal forebrain, are specifically susceptible in some neurodegenerative diseases, such as in Alzheimer’s disease (AD). Here, we studied the cholinergic system lesion effects of five familial AD mutations in 5XFAD mice, a transgenic mouse model of AD. Although the cholinergic system has been studied in this mouse model, the cholinergic deficits in AD mice have never been systematically mapped in a whole-brain three-dimensional (3D) reconstruction. Using the 3D reconstruction technology combined with immunohistochemistry (3D-IHC) and design-based stereology, we comprehensively compared the differences of the cholinergic neurons and fibers between the 5XFAD mice and C57BL/6 control mice at different age. Here, we found that the lesion of cholinergic fibers occurred earlier than the cholinergic neuron loss in 5XFAD mice. The cholinergic fiber lesions in the AD mice started sequentially in amygdala, cortex, hippocampus, and then basal forebrain. However, the basal forebrain was the first brain region observed with cholinergic neuron loss at the age of 9 months in 5XFAD mice, whereas such phenomenon first occurred at the age of 15 months in C57BL/6 control mice. Moreover, using 3D reconstruction to compare the lesion of cholinergic system of aged 5XFAD and C57BL/6 control mice, it is intuitive to notice the pathologic regions and severity of lesion. Therefore, the 3D-IHC provides detailed overview of the cholinergic neurons in the whole mouse brain, which will contribute to the study of the developing and pathologic mouse brain.

Cholinergic system is very important for many higher brain functions, including learning and memory. Cholinergic neurons, especially those in the basal forebrain, are specifically susceptible in some neurodegenerative diseases, such as in Alzheimer's disease (AD). Here, we studied the cholinergic system lesion effects of five familial AD mutations in 5XFAD mice, a transgenic mouse model of AD. Although the cholinergic system has been studied in this mouse model, the cholinergic deficits in AD mice have never been systematically mapped in a whole-brain three-dimensional (3D) reconstruction. Using the 3D reconstruction technology combined with immunohistochemistry (3D-IHC) and design-based stereology, we comprehensively compared the differences of the cholinergic neurons and fibers between the 5XFAD mice and C57BL/6 control mice at different age. Here, we found that the lesion of cholinergic fibers occurred earlier than the cholinergic neuron loss in 5XFAD mice. The cholinergic fiber lesions in the AD mice started sequentially in amygdala, cortex, hippocampus, and then basal forebrain. However, the basal forebrain was the first brain region observed with cholinergic neuron loss at the age of 9 months in 5XFAD mice, whereas such phenomenon first occurred at the age of 15 months in C57BL/6 control mice. Moreover, using 3D reconstruction to compare the lesion of cholinergic system of aged 5XFAD and C57BL/6 control mice, it is intuitive to notice the pathologic regions and severity of lesion. Therefore, the 3D-IHC provides detailed overview of the cholinergic neurons in the whole mouse brain, which will contribute to the study of the developing and pathologic mouse brain.

Clinical data have shown women are more susceptible to depression. This study was performed to identify differentially regulated proteins from hippocampus in chronic unpredicted mild stress (CUMS)-exposed male and female young rats. After 7 weeks of CUMS, depressed male (M-D) and female rats (F-D) and unstressed male (M-C) and female controls (F-C) were studied. By proteomics analysis, 74 differential proteins in F-C/M-C, 79 in F-D/M-D, 77 in F-D/F-C, and 32 in M-D/M-C were found. Further, the synapse-related proteins, cytoskeleton protein tau, and stress-related kinases in hippocampus were assayed by Western blotting. F-C rats were found to have lower levels of metabotropic glutamate receptor 1 (mGluR1) and mGluR2 and higher levels of N-methyl-D-aspartate receptor 2B (NR2B), synapsin1, total tau, and dephosphorylated tau than M-C rats. Both F-D and M-D rats had lower levels of glutamate transporter SLC1α2, mGluR1, and mGluR2, and higher levels of total tau and phosphorylated tau than their controls. Compared with their controls, M-D rats had lower NR1 and higher NR2B, and F-D rats had lower NR2A, NR2B, PSD95, and synapsin1. F-C rats had higher JNK and lower phosphorylation levels of ERK at Thr202/Thr204, JNK at Thr183/Thr185, and GSK-3β at Ser9 than M-C ones. Both M-D and F-D rats had decreased phosphorylation of ERK at Thr202/Thr204 and GSK-3β at Ser9, and increased JNK phosphorylation at Thr183/Thr185 compared with their controls. All these data illustrate the biochemical complexity behind the genders, and may also aid in the development of more accurate treatment strategies for depression.

Ischemic stroke, or a brain attack, is the third leading cause of death in developed countries. A critical feature of the disease is a highly selective pattern of neuronal loss; certain identifiable subsets of neurons--particularly CA1 pyramidal neurons in the hippocampus are severely damaged, whereas others remain intact. A key step in this selective neuronal injury is Ca2+/Zn2+ entry into vulnerable neurons through alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels, a principle subtype of glutamate receptors. AMPA receptor channels are assembled from glutamate receptor (GluR)1, -2, -3, and -4 subunits. Circumstance data have indicated that the GluR2 subunits dictate Ca2+/Zn2+ permeability of AMPA receptor channels and gate injurious Ca2+/Zn2+ signals in vulnerable neurons. Therefore, targeting to the AMPA receptor subunit GluR2 can be considered a practical strategy for stroke therapy.