Neng-Wei Hu

Synaptic memory mechanisms : Alzheimer's disease amyloid β-peptide-induced dysfunction

There is growing evidence that mild cognitive impairment in early AD (Alzheimers disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Abeta (amyloid beta-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Abeta oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Abeta, the alphav integrin extracellular cell matrix-binding protein and the cytokine TNFalpha (tumour necrosis factor alpha) type-1 death receptor mediate Abeta oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFalpha or genetic knockout of TNF-R1s (type-1 TNFalpha receptors) prevented Abeta-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to alphav-containing integrins abrogated LTP block by Abeta. Protection against the synaptic plasticity-disruptive effects of soluble Abeta was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of Abeta oligomers in preclinical AD.

GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo

Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimers disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-β protein (Aβ) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Aβ in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Aβ1–42 -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFα mediates this deleterious action of Aß was provided by the ability of TNFα antagonists to prevent Aβ1–42 inhibition of plasticity and the abrogation of a similar disruptive effect of TNFα using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFα, Aβ1–42 did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimers disease.

Alzheimer’s Disease Amyloid β-Protein and Synaptic Function

Alzheimer’s disease (AD) is characterized neuropathologically by the deposition of different forms of amyloid β-protein (Aβ) including variable amounts of soluble species that correlate with severity of dementia. The extent of synaptic loss in the brain provides the best morphological correlate of cognitive impairment in clinical AD. Animal research on the pathophysiology of AD has therefore focussed on how soluble Aβ disrupts synaptic mechanisms in vulnerable brain regions such as the hippocampus. Synapic plasticity in the form of persistent activity-dependent increases or decreases in synaptic strength provide a neurophysiological substrate for hippocampal-dependent learning and memory. Acute treatment with human-derived or chemically prepared soluble Aβ that contains certain oligomeric assemblies, potently and selectively disrupts synaptic plasticity causing inhibition of long-term potentiation (LTP) and enhancement of long-term depression (LTD) of glutamatergic transmission. Over time these and related actions of Aβ have been implicated in reducing synaptic integrity. This review addresses the involvement of neurotransmitter intercellular signaling in mediating or modulating the synaptic plasticity disrupting actions of soluble Aβ, with particular emphasis on the different roles of glutamatergic and cholinergic mechanisms. There is growing evidence to support the view that NMDA and possibly nicotinic receptors are critically involved in mediating the disruptive effect of Aβ and that targeting muscarinic receptors can indirectly modulate Aβ’s actions. Such studies should help inform ongoing and future clinical trials of drugs acting through the glutamatergic and cholinergic systems.

mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo

NMDA-type glutamate receptors (NMDARs) are currently regarded as paramount in the potent and selective disruption of synaptic plasticity by Alzheimer’s disease amyloid β-protein (Aβ). Non-NMDAR mechanisms remain relatively unexplored. Here we describe how Aβ facilitates NMDAR-independent long-term depression of synaptic transmission in the hippocampus in vivo. Synthetic Aβ and Aβ in soluble extracts of Alzheimer’s disease brain usurp endogenous acetylcholine muscarinic receptor-dependent long-term depression, to enable long-term depression that required metabotropic glutamate-5 receptors (mGlu5Rs). We also find that mGlu5Rs are essential for Aβ-mediated inhibition of NMDAR-dependent long-term potentiation in vivo. Blocking Aβ binding to cellular prion protein with antibodies prevents the facilitation of long-term depression. Our findings uncover an overarching role for Aβ-PrPC-mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary.

Soluble amyloid-β peptides potently disrupt hippocampal synaptic plasticity in the absence of cerebrovascular dysfunction in vivo

Long before the onset of clinical Alzheimers disease non-fibrillar, soluble assembly states of amyloid-beta (Abeta) peptides are believed to cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Since many of the risk factors for Alzheimers disease are vascular, impairment of cerebral blood flow by soluble Abeta has been proposed to be critical in triggering these early changes. However, it is not known if soluble Abeta can affect cerebrovascular function at the concentrations required to cause inhibition of synaptic plasticity mechanisms believed to underlie the early cognitive deficits of Alzheimers disease. Here we developed a new method to simultaneously assess the ability of soluble Abeta to impair plasticity at synapses and to affect resting and activity-dependent local blood flow in the rat hippocampus in vivo. Intracerebroventricular injection of soluble synthetic Abeta(40) dimers rapidly inhibited plasticity of excitatory synaptic transmission at doses (10-42 pmol) comparable to natural Abeta, but failed to affect vascular function measured using laser-Doppler flowmetry (LDF). Like wild-type Abeta(40), the more vasculotropic Abeta produced by people with familial hemorrhagic stroke of the Dutch type (Abeta(40)E22Q), impaired hippocampal plasticity without causing a significant change in local blood flow. Furthermore, neither resting nor activation-evoked hippocampal perfusion was affected by soluble Abeta(42), even at a concentration that markedly (25%) reduced baseline synaptic transmission. These findings demonstrate that the putative synaptotoxic soluble Abeta species of early Alzheimers disease cause synaptic dysfunction in the absence of detectible changes in local blood flow. This strongly indicates that early cognitive deficits can be caused by soluble Abeta independently of deleterious effects on cerebrovascular dynamics.

Glutamate receptors in preclinical research on Alzheimer's disease: update on recent advances.

The cognitive and related symptoms of Alzheimers disease are mainly attributable to synaptic failure. Here we review recent research on how the Alzheimers disease amyloid ß-protein (Aß) affects glutamate receptors and fast excitatory synaptic transmission and plasticity of that transmission. l-glutamate, the main excitatory neurotransmitter in the brain, has long been implicated in causing NMDA receptor-mediated excitotoxicity leading to neurodegeneration in the late stages of the disease. However there is now extensive evidence that soluble Aß oligomers disrupt synaptic transmission and especially synaptic plasticity via non-excitotoxic glutamatergic mechanisms. New data highlight the relatively selective involvement of certain glutamate receptor subtypes including GluN2B (NR2B) subunit-containing NMDA receptors and mGlu5 receptors. Aß exerts direct and indirect effects on synaptic plasticity-related glutamate receptor signaling and trafficking between different neuronal compartments. For example, Aß-induced ectopic NMDA and mGlu receptor-mediated signaling coupled with caspase-3 activation may cause inhibition of long-term potentiation and facilitation of long-term depression. Intriguingly, some of the disruptive synaptic actions of Aß have been found to be dependent on endogenous tau located in dendrites or spines. Given the role of glutamatergic transmission in regulating Aß production and release, future therapies targeting glutamate offer the opportunity to remedy both mis-processing of Aß and cellular mechanisms of synaptic failure in early AD.

Alzheimer's disease Aβ assemblies mediating rapid disruption of synaptic plasticity and memory

Alzheimer’s disease (AD) is characterized by episodic memory impairment that often precedes clinical diagnosis by many years. Probing the mechanisms of such impairment may provide much needed means of diagnosis and therapeutic intervention at an early, pre-dementia, stage. Prior to the onset of significant neurodegeneration, the structural and functional integrity of synapses in mnemonic circuitry is severely compromised in the presence of amyloidosis. This review examines recent evidence evaluating the role of amyloid-ß protein (Aβ) in causing rapid disruption of synaptic plasticity and memory impairment. We evaluate the relative importance of different sizes and conformations of Aβ, including monomer, oligomer, protofibril and fibril. We pay particular attention to recent controversies over the relevance to the pathophysiology of AD of different water soluble Aβ aggregates and the importance of cellular prion protein in mediating their effects. Current data are consistent with the view that both low-n oligomers and larger soluble assemblies present in AD brain, some of them via a direct interaction with cellular prion protein, cause synaptic memory failure. At the two extremes of aggregation, monomers and fibrils appear to act in vivo both as sources and sinks of certain metastable conformations of soluble aggregates that powerfully disrupt synaptic plasticity. The same principle appears to apply to other synaptotoxic amyloidogenic proteins including tau, α-synuclein and prion protein.

Switching off LTP: mGlu and NMDA Receptor–Dependent Novelty Exploration–Induced Depotentiation in the Rat Hippocampus

Both electrically induced synaptic long-term potentiation (LTP) and long-term depression have been extensively studied as models of the cellular basis of learning and memory mechanisms. Recently, considerable interest has been generated by the possibility that the activity-dependent persistent reversal of previously established synaptic LTP (depotentiation) may play a role in the time- and state-dependent erasure of memory. Here, we examined the requirement for glutamate receptor activation in experience-induced reversal of previously established LTP in the CA1 area of the hippocampus of freely behaving rats. Continuous exploration of non-aversive novelty for ~30 min, which was associated with hippocampal activation as measured by increased theta power in the electroencephalogram, triggered a rapid and persistent reversal of high frequency stimulation-induced LTP both at apical and basal synapses. Blockade of metabotropic glutamate (mGlu) receptors with mGlu5 subtype-selective antagonists, or N-methyl-D-aspartate (NMDA) receptors with GluN2B subunit-selective antagonists, prevented novelty-induced depotentiation. These findings strongly indicate that activation of both mGlu5 receptors and GluN2B-containing NMDA receptors is required for experience-triggered induction of depotentiation at CA3-CA1 synapses. The mechanistic concordance of the present and previous studies of experience-induced and electrically induced synaptic depotentiation helps to integrate our understanding of the neurophysiological underpinnings of learning and memory.

Extracellular Forms of Aβ and Tau from iPSC Models of Alzheimer’s Disease Disrupt Synaptic Plasticity

Summary The early stages of Alzheimer’s disease are associated with synaptic dysfunction prior to overt loss of neurons. To identify extracellular molecules that impair synaptic plasticity in the brain, we studied the secretomes of human iPSC-derived neuronal models of Alzheimer’s disease. When introduced into the rat brain, secretomes from human neurons with either a presenilin-1 mutation, amyloid precursor protein duplication, or trisomy of chromosome 21 all strongly inhibit hippocampal long-term potentiation. Synaptic dysfunction caused by presenilin-1 mutant and amyloid precusor protein duplication secretomes is mediated by Aβ peptides, whereas trisomy of chromosome 21 (trisomy 21) neuronal secretomes induce dysfunction through extracellular tau. In all cases, synaptotoxicity is relieved by antibody blockade of cellular prion protein. These data indicate that human models of Alzheimer’s disease generate distinct proteins that converge at the level of cellular prion protein to induce synaptic dysfunction in vivo.

Alzheimer's disease human brain beta-amyloid-containing extracts inhibit hippocampal long-term potentiation in rats in vivo: Relationship between soluble and insoluble preparations

age-matched control mice. Results: We found an age-dependent decrease in calbindin levels in ZnT3-/mouse hippocampus compared to agematched control mice. There was no difference at three months of age, a 12% decrease at six months of age, an 18% decrease at twelve months of age, and a 16% decrease at 15 months of age. Analysis of neuropeptide Y levels indicates an age-dependent increase in ZnT3-/mouse hippocampus compared to age-matched control mice. Therewas no difference at three and six months of age, a 16% increase at twelve months of age and a 43% increase at 15months of age.Conclusions:The finding of alterations in protein levels consistent with seizure activity in ZnT3-/mice indicates that sequestration of zinc may result in reduced excitatory modulation by zinc leading to hyperexcitability and increased seizure activity. This provides new insight into the mechanisms responsible for the seizure activity common in AD patients and potential targets for therapeutic interventions to ameliorate AD-related seizures.