Synaptic Injury Research Articles

The Contribution of α-Synuclein Spreading to Parkinson's Disease Synaptopathy.

Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson's disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related to α-synuclein deposition at synaptic sites. Indeed, α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate that α-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillary α-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior could further contribute to synaptic failure in PD and other synucleinopathies. This review describes the major findings supporting the occurrence of α-synuclein pathology propagation in PD and discusses how this phenomenon could induce or contribute to synaptic injury and degeneration.

Recent advances in cerebrospinal fluid biomarkers for the detection of preclinical Alzheimer's disease.

The concept of preclinical Alzheimer's disease has emerged to describe the long 'silent' phase of the disease when significant pathophysiological changes occur in the brain but clinical symptoms are not yet manifest. In this review, a summary of the recent advances in cerebrospinal fluid (CSF) biomarker-based diagnostics of preclinical Alzheimer's disease will be presented. The association between core CSF biomarkers of Alzheimer's disease and between CSF and neuroimaging markers has been a major focus of various recently published studies in cognitively healthy individuals. Longitudinal results from several research groups suggest that CSF Aβ42 is altered early in preclinical Alzheimer's disease, even preceding changes on amyloid PET imaging. In line with the proposed NIA-AA criteria, elevated tau levels and/or Aβ/tau interactions appear to be a prerequisite for neurodegeneration and future cognitive decline. Novel candidate CSF markers, including markers of neuronal and synaptic injury as well as neuroinflammation, may complement CSF-based diagnostics in preclinical Alzheimer's disease. Further longitudinal research is necessary to delineate the temporal changes of core and candidate CSF biomarkers in preclinical Alzheimer's disease and to investigate their association with established and emerging neuroimaging markers as well as with comorbidities and other risk factors for age-related cognitive decline.

Particulate matter (PM2.5) exposure season-dependently induces neuronal apoptosis and synaptic injuries

Epidemiological studies have shown that particulate matter 2.5 (PM2.5) not only increases the incidence of cardiopulmonary illnesses but also relates to the development of neurodegenerative diseases. Considering that PM2.5 is highly heterogeneous with regional disparity and seasonal variation, we investigated whether PM2.5 exposure induced neuronal apoptosis and synaptic injuries in a season-dependent manner. The results indicated that PM2.5 altered the expression of apoptosis-related proteins (mainly bax and bcl-2), activated caspase-3 and caused neuronal apoptosis. Additionally, PM2.5 decreased the levels of synaptic structural protein postsynaptic density (PSD-95) and synaptic functional protein N-methyl-D-aspartate (NMDA) receptor subunit (NR2B) expression. These effects occurred in a season-dependent manner, and PM2.5 collected from the winter showed the strongest changes. Furthermore, the effect was coupled with the inhibition of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and phosphorylated cAMP-response element binding protein (p-CREB). Based on the findings, we analyzed the correlations between the chemical composition of PM2.5 samples and the biological effects, and confirmed that winter PM2.5 played a major role in causing neuronal apoptosis and synaptic injuries among different season samples.

Pro-inflammatory cytokines in Alzheimer's disease

Alzheimer's disease (AD), the most common progressive neurodegenerative disorder in the elderly, is clinically characterized by progressive impairment of cognitive functions, including reduced critical capacity, weakness of decision-making and problem orientation, while in the more advanced stages it is accompanied by behavioral disorders and impaired verbal ability. Neuropathological characteristics of the disease are the neurofibrillary tangles (NFT), the neuritic plaques (NP), the prominent synaptic loss and eventually the neuronal loss. The presence of inflammatory process seems to be playing important role in the progression of the disease. This process is directed by the activated glial cells and it leads to the overproduction of acute phase proteins, complement factors activation and induction of inflammatory enzyme systems. These inflammatory factors can contribute to neuronal dysfunction and cell death. Cytokines belong to the acute phase proteins, which are secreted from glial cells. They can either strengthen the inflammatory reaction or suppress it, adjusting the intensity and duration of the immune response. In the category of cytokines belong several interleukins (ILs) and various factors (TNF-α, TGF-β). Interleukins are involved in complex intercellular interactions among neurons, microglia and astrocytes, as well as intracellular signal transduction events, which are necessary to promote the inflammatory cascade characteristic of AD neuropathology. It has been observed that increased levels of pro- inflammatory cytokines, including tumor necrosis factor (TNF), interleukin 1β (IL-1β), interleukin 6 (IL-6) and interferon γ (IFN-γ), may suspend phagocytosis of amyloid Aβ in brains of patients with AD. Thus, it may interfere with the effective removal of plaque from microglia, promote astrogliosis and neural death. Normally, during immune surveillance, a balance is maintained between pro- and antiinflammatory influences. Yet, during AD, the abnormal accumulation of soluble amyloid oligomers triggers excessive release of pro inflammatory factors, such as cytokines and other acute-phase reactants, out of proportion to the regulatory components, such as IL-4, IL-10, receptor antagonists, interleukin inhibitors and others, ultimately leading to neuronal and synaptic injury and loss and cognitive decline. These changes in the brain parenchyma are often accompanied by changes in levels of these inflammatory proteins in peripheral blood. Even though literature is presenting conflicting studies, efforts are being made for the detection of cytokines in peripheral blood and association of their levels with the progression of AD. Inflammatory pathways, involving the signaling of cytokines, could be potential targets for the prevention of AD and the development of new therapies. The aim of the present work is to review studies indicating a correlation between these inflammatory agents and AD pathogenesis.

CROSSTALK OF MITOCHONDRIA TO SYNAPTIC DYSFUNCTION IN ALZHEIMER DISEASE

Diabetes is considered to be a risk factor in Alzheimer’s disease (AD) pathogenesis and has adverse effects on the brain, especially the hippocampus, which is particularly susceptible to synaptic injury and cognitive dysfunction. The underlying mechanisms and strategies to rescue such injury and dysfunction are not well understood. Combination of in vitro neuronal culture and in vivo diabetes and Alzheimer's disease mouse models to study mitochondrial function, dynamics, axonal mitochondrial transport, and synaptic function including pre- and post-synaptic morphology and activity. To detemine the effect of AD-related mitochondrial defects, we also examined AD- or MCI-derived mitochondria in neuronal cybrid cells incoporated with mitochondria from platelets of patients with Alzheimer's disease. Our most recent studies point to a novel role of mitochondrial dynamics and transport in diabetes- and AD-induced synaptic impairment. Inhibition of excessive mitochondrial fission induced by hyperglycemia, oxidative stress, and amyloid beta in vitro and in vivo diabetes and AD models significantly improves mitochondrial and synaptic function. Additionally, blockade of mitochondrial membrane transition pore restores synaptic mitochondrial function and synaptic transmission. Furthermore, inhibition of either excessive mitochondrial fission or cyclophilin D-induced mitochondrial transition pore improves AD-mitochondrial defects. Blockade of activation of MAPkinase (p38 phosphorylation) reverses these detrimental effects, suggesting the contribution of oxidative stress-induced signaling to mitochondrial dysfunction relevant to AD pathology. Our studies indicate that synaptic mitochondria play a key role in synaptic plasticity and transmission in diabetes- and Alzheimer's disease-insulted abnormalities. Thus, exploration the mechanisms behind diabetes-induced synaptic deficit may provide a novel treatment of mitochondrial and synaptic injury in patients with diabetes beyond management of high glucose. Targeting mitochondria-mediated alterations in dynamics, mitochondrial transition pore, and bioenergy may be a potential for the tratement of diabetes as well as Alzheimer's disease. This study is supported by NIH.

APOE ε4 carriers may undergo synaptic damage conferring risk of Alzheimer's disease

IntroductionPathogenesis of Alzheimer's disease (AD) in apolipoprotein E ε4 (APOE ε4) carriers remains unclear. We hypothesize that APOE isoforms have differential effects on synaptic function. MethodsWe compared levels of CSF neurogranin (Ng) between APOE ε4 carriers and noncarriers in 399 subjects with normal cognition, mild cognitive impairment (MCI), and AD. We examined associations between Ng levels and age, education, gender, CSF-Aβ42, and tau protein. ResultsNeurogranin levels were significantly higher in APOE ε4 carriers compared to APOE ε4 noncarriers with MCI. Levels of Ng between the APOE ε4 carriers and APOE ε4 noncarriers with AD did not differ. Ng levels were correlated with MMSE and levels of tau and Aβ42. DiscussionSignificantly higher CSF Ng levels in APOE ε4 carriers with MCI may reflect synaptic injury underlying early cognitive impairment. Neurogranin may be an early biomarker of AD and important for disease diagnosis and timing of intervention in APOE ε4 carriers.

Tinnitus is associated with reduced sound level tolerance in adolescents with normal audiograms and otoacoustic emissions.

Recent neuroscience research suggests that tinnitus may reflect synaptic loss in the cochlea that does not express in the audiogram but leads to neural changes in auditory pathways that reduce sound level tolerance (SLT). Adolescents (N = 170) completed a questionnaire addressing their prior experience with tinnitus, potentially risky listening habits, and sensitivity to ordinary sounds, followed by psychoacoustic measurements in a sound booth. Among all adolescents 54.7% reported by questionnaire that they had previously experienced tinnitus, while 28.8% heard tinnitus in the booth. Psychoacoustic properties of tinnitus measured in the sound booth corresponded with those of chronic adult tinnitus sufferers. Neither hearing thresholds (≤15 dB HL to 16 kHz) nor otoacoustic emissions discriminated between adolescents reporting or not reporting tinnitus in the sound booth, but loudness discomfort levels (a psychoacoustic measure of SLT) did so, averaging 11.3 dB lower in adolescents experiencing tinnitus in the acoustic chamber. Although risky listening habits were near universal, the teenagers experiencing tinnitus and reduced SLT tended to be more protective of their hearing. Tinnitus and reduced SLT could be early indications of a vulnerability to hidden synaptic injury that is prevalent among adolescents and expressed following exposure to high level environmental sounds.

Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer's disease.

F1FO-ATP synthase is critical for mitochondrial functions. The deregulation of this enzyme results in dampened mitochondrial oxidative phosphorylation (OXPHOS) and activated mitochondrial permeability transition (mPT), defects which accompany Alzheimer’s disease (AD). However, the molecular mechanisms that connect F1FO-ATP synthase dysfunction and AD remain unclear. Here, we observe selective loss of the oligomycin sensitivity conferring protein (OSCP) subunit of the F1FO-ATP synthase and the physical interaction of OSCP with amyloid beta (Aβ) in the brains of AD individuals and in an AD mouse model. Changes in OSCP levels are more pronounced in neuronal mitochondria. OSCP loss and its interplay with Aβ disrupt F1FO-ATP synthase, leading to reduced ATP production, elevated oxidative stress and activated mPT. The restoration of OSCP ameliorates Aβ-mediated mouse and human neuronal mitochondrial impairments and the resultant synaptic injury. Therefore, mitochondrial F1FO-ATP synthase dysfunction associated with AD progression could potentially be prevented by OSCP stabilization.

Phosphoinositides: Two-Path Signaling in Neuronal Response to Oligomeric Amyloid β Peptide.

We have previously demonstrated that oligomeric amyloid β peptide (oAβ) together with iron overload generates synaptic injury and activation of several signaling cascades. In this work, we characterized hippocampal neuronal response to oAβ. HT22 neurons exposed to 500nM oAβ showed neither increased lipid peroxidation nor altered mitochondrial function. In addition, biophysical studies showed that oAβ did not perturb the lipid order of the membrane. Interestingly, although no neuronal damage could be demonstrated, oAβ was found to trigger bifurcated phosphoinositide-dependent signaling in the neuron, on one hand, the phosphorylation of insulin receptor, the phosphatidylinositol 3-kinase (PI3K)-dependent activation of Akt, its translocation to the nucleus and the concomitant phosphorylation, inactivation, and nuclear exclusion of the transcription factor Forkhead Box O3a (FoxO3a), and on the other, phosphoinositide-phospholipase C (PI-PLC)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Pharmacological manipulation of the signaling cascades was used in order to better characterize the role of oAβ-activated signals, and mitochondrial function was determined as a measure of neuronal viability. The inhibition of PI3K, PI-PLC, and general phosphoinositide metabolism impaired neuronal mitochondrial function. Furthermore, increased oAβ-induced cell death was observed in the presence of phosphoinositide metabolism inhibition. Our results allow us to conclude that oAβ triggers the activation of phosphoinositide-dependent signaling, which results in the subsequent activation of neuroprotective mechanisms that could be involved in the determination of neuronal fate.

Untangling the Web: Toxic and Protective Effects of Neuroinflammation and PGE2 Signaling in Alzheimer's Disease.

The neuroinflammatory response has received increasing attention as a key factor in the pathogenesis of Alzheimer's disease (AD). Microglia, the innate immune cells and resident phagocytes of the brain, respond to accumulating Aβ peptides by generating a nonresolving inflammatory response. While this response can clear Aβ peptides from the nervous system in some settings, its failure to do so in AD accelerates synaptic injury, neuronal loss, and cognitive decline. The complex molecular components of this response are beginning to be unraveled, with identification of both damaging and protective roles for individual components of the neuroinflammatory response. Even within one molecular pathway, contrasting effects are often present. As one example, recent studies of the inflammatory cyclooxygenase-prostaglandin pathway have revealed both beneficial and detrimental effects dependent on the disease context, cell type, and downstream signaling pathway. Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenases, are associated with reduced AD risk when taken by cognitively normal populations, but additional clinical and mouse model studies have added complexities and caveats to this finding. Downstream of cyclooxygenase activity, prostaglandin E2 signaling exerts both damaging pro-inflammatory and protective anti-inflammatory effects through actions of specific E-prostanoid G-protein coupled receptors on specific cell types. These complexities underscore the need for careful study of individual components of the neuroinflammatory response to better understand their contribution to AD pathogenesis and progression.

Synaptosomal Mitochondrial Dysfunction in 5xFAD Mouse Model of Alzheimer's Disease.

Brain mitochondrial dysfunction is hallmark pathology of Alzheimer’s disease (AD). Recently, the role of synaptosomal mitochondrial dysfunction in the development of synaptic injury in AD has received increasing attention. Synaptosomal mitochondria are a subgroup of neuronal mitochondria specifically locating at synapses. They play an essential role in fueling synaptic functions by providing energy on the site; and their defects may lead to synaptic failure, which is an early and pronounced pathology in AD. In our previous studies we have determined early synaptosomal mitochondrial dysfunction in an AD animal model (J20 line) overexpressing human Amyloid beta (Aβ), the key mediator of AD. In view of the limitations of J20 line mice in representing the full aspects of amyloidopathy in AD cases, we employed 5xFAD mice which are thought to be a desirable paradigm of amyloidopathy as seen in AD subjects. In addition, we have also examined the status of synaptosomal mitochondrial dynamics as well as Parkin-mediated mitophagy which have not been previously investigated in this mouse model. In comparison to nontransgenic (nonTg mice), 5xFAD mice demonstrated prominent synaptosomal mitochondrial dysfunction. Moreover, synaptosomal mitochondria from the AD mouse model displayed imbalanced mitochondrial dynamics towards fission along with activated Parkin and LC3BII recruitment correlating to spatial learning & memory impairments in 5xFAD mice in an age-dependent manner. These results suggest that synaptosomal mitochondrial deficits are primary pathology in Aβ-rich environments and further confirm the relevance of synaptosomal mitochondrial deficits to the development of AD.

Synaptic Mechanisms of Blast-Induced Brain Injury.

Blast wave-induced traumatic brain injury (TBI) is one of the most common injuries to military personnel. Brain tissue compression/tension due to blast-induced cranial deformations and shear waves due to head rotation may generate diffuse micro-damage to neuro-axonal structures and trigger a cascade of neurobiological events culminating in cognitive and neurodegenerative disorders. Although diffuse axonal injury is regarded as a signature wound of mild TBI (mTBI), blast loads may also cause synaptic injury wherein neuronal synapses are stretched and sheared. This synaptic injury may result in temporary disconnect of the neural circuitry and transient loss in neuronal communication. We hypothesize that mTBI symptoms such as loss of consciousness or dizziness, which start immediately after the insult, could be attributed to synaptic injury. Although empirical evidence is beginning to emerge; the detailed mechanisms underlying synaptic injury are still elusive. Coordinated in vitro–in vivo experiments and mathematical modeling studies can shed light into the synaptic injury mechanisms and their role in the potentiation of mTBI symptoms.

The cell-permeable Aβ1-6A2VTAT(D) peptide reverts synaptopathy induced by Aβ1-42wt

Alzheimer disease (AD) is the most prevalent form of dementia. Loss of hippocampal synapses is the first neurodegenerative event in AD. Synaptic loss has been associated with the accumulation in the brain parenchyma of soluble oligomeric forms of amyloid β peptide (Aβ1-42wt). Clinical observations have shown that a mutation in the APP protein (A673V) causes an early onset AD-type dementia in homozygous carriers while heterozygous carriers are unaffected. This mutation leads to the formation of mutated Aβ peptides (Aβ1-42A2V) in homozygous patients, while in heterozygous subjects both Aβ1-42wt and Aβ1-42A2V are present. To better understand the impact of the A673V mutation in AD, we analyzed the synaptotoxic effect of oligomers formed by aggregation of different Aβ peptides (Aβ1-42wt or Aβ1-42A2V) and the combination of the two Aβ1-42MIX (Aβ1-42wt and Aβ1-42A2V) in an in vitro model of synaptic injury. We showed that Aβ1-42A2V oligomers are more toxic than Aβ1-42wt oligomers in hippocampal neurons, confirming the results previously obtained in cell lines. Furthermore, we reported that oligomers obtained by the combination of both wild type and mutated peptides (Aβ1-42MIX) did not exert synaptic toxicity. We concluded that the combination of Aβ1-42wt and Aβ1-42A2V peptides hinders the toxicity of Aβ1-42A2V and counteracts the manifestation of synaptopathy in vitro. Finally we took advantage of this finding to generate a cell-permeable peptide for clinical application, by fusing the first six residues of the Aβ1-42A2V to the TAT cargo sequence (Aβ1-6A2VTAT(D)).Noteworthy, the treatment with Aβ1-6A2VTAT(D) confers neuroprotection against both in vitro and in vivo synaptopathy models. Therefore Aβ1-6A2VTAT(D) may represent an innovative therapeutic tool to prevent synaptic degeneration in AD.

HIV-1 gp120Bal down-Regulates Phosphorylated NMDA Receptor Subunit 1 in Cortical Neurons via Activation of Glutamate and Chemokine Receptors.

HIV-1 envelope glycoprotein gp120 (gp120) is a major virulence protein implicated in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Although gp120 has been suggested to cause synaptic and neuronal injuries by disrupting NMDA receptor (NMDAR) function, the underlying mechanism is unclear. Here, we show that gp120Bal down-regulates the phosphorylation of the NMDAR subunit1 NR1 (at Ser896 and Ser897), which is essential for NMDAR function. This effect of gp120Bal is blocked by specific antagonists of both NMDA and AMPA receptors, indicating a critical role of synaptic activation. Furthermore, AMD3100 and maraviroc, antagonists of CCR5 and CXCR4 chemokine receptors, respectively, inhibit the effect of gp120Bal on NR1, suggesting that CXCR4 and CCR5 activation are involved. These findings may provide mechanistic insights into the synaptopathogenesis caused by HIV-1 infection.

New tricks from an old dog: Another synaptotoxic fragment from APP.

In a surprising twist, a hitherto unrecognized cleavage of the amyloid precursor protein (APP) by η-secretase, followed by α- or β-secretase cleavage releases a novel APP proteolytic fragment, Aη, which causes synaptic injury.

β-Asarone Mitigates Amyloidosis and Downregulates RAGE in a Transgenic Mouse Model of Alzheimer's Disease.

Elevated β-amyloid (Aβ) is a hallmark of Alzheimer's disease (AD). Recent evidence has suggested that the receptor of advanced glycation end products (RAGE) is a key target for Aβ-induced perturbation in AD, and blockade of RAGE significantly alleviates synaptic injury. Our previous study has suggested that β-asarone could reduce neuronal apoptosis and improve memory deficits in β-amyloid precursor protein and presenilin-1 (APP/PS1) double transgenic AD-model mice. In the present study, we evaluated the effects of β-asarone on amyloidosis in APP/PS1 mice. We found that the survival of neurons of APP/PS1 mice was improved by β-asarone, meanwhile, β-asarone decreased Aβ deposition and down-regulated Aβ1-42 levels in cortex and hippocampus of APP/PS1 mice brain. Interestingly, the level of RAGE was also significantly down-regulated by β-asarone. Our findings suggest that β-asarone might be effective for the treatment of AD, and the decreasing effects of β-asarone on Aβ might associate with its down-regulation of RAGE.

Inflammatory Cyclooxygenase Activity and PGE2 Signaling in Models of Alzheimer's Disease.

The inflammatory response is a fundamental driving force in the pathogenesis of Alzheimer’s disease (AD). In the setting of accumulating immunogenic Aß peptide assemblies, microglia, the innate immune cells of the brain, generate a non-resolving immune response and fail to adequately clear accumulating Aß peptides, accelerating neuronal and synaptic injury. Pathological, biomarker, and imaging studies point to a prominent role of the innate immune response in AD development, and the molecular components of this response are beginning to be unraveled. The inflammatory cyclooxygenase-PGE2 pathway is implicated in pre-clinical development of AD, both in epidemiology of normal aging populations and in transgenic mouse models of Familial AD. The cyclooxygenase-PGE2 pathway modulates the inflammatory response to accumulating Aß peptides through actions of specific E-prostanoid G-protein coupled receptors.

NR2B-dependent cyclophilin D translocation suppresses the recovery of synaptic transmission after oxygen–glucose deprivation

N-methyl d-aspartate receptor (NMDA) subunit 2B (NR2B)-containing NMDA receptors and mitochondrial protein cyclophilin D (CypD) are well characterized in mediating neuronal death after ischemia, respectively. However, whether and how NR2B and CypD work together in mediating synaptic injury after ischemia remains elusive. Using an ex vivo ischemia model of oxygen–glucose deprivation (OGD) in hippocampal slices, we identified a NR2B-dependent mechanism for CypD translocation onto the mitochondrial inner membrane. CypD depletion (CypD null mice) prevented OGD-induced impairment in synaptic transmission recovery. Overexpression of neuronal CypD mice (CypD+) exacerbated OGD-induced loss of synaptic transmission. Inhibition of CypD-dependent mitochondrial permeability transition pore (mPTP) opening by cyclosporine A (CSA) attenuated ischemia-induced synaptic perturbation in CypD+ and non-transgenic (non-Tg) mice. The treatment of antioxidant EUK134 to suppress mitochondrial oxidative stress rescued CypD-mediated synaptic dysfunction following OGD in CypD+ slices. Furthermore, OGD provoked the interaction of CypD with P53, which was enhanced in slices overexpressing CypD but was diminished in CypD-null slices. Inhibition of p53 using a specific inhibitor of p53 (pifithrin-μ) attenuated the CypD/p53 interaction following OGD, along with a restored synaptic transmission in both non-Tg and CypD+ hippocampal slices. Our results indicate that OGD-induced CypD translocation potentiates CypD/P53 interaction in a NR2B dependent manner, promoting oxidative stress and loss of synaptic transmission. We also evaluate a new ex vivo chronic OGD-induced ischemia model for studying the effect of oxidative stress on synaptic damage.

Induction of Interleukin-1β by Human Immunodeficiency Virus-1 Viral Proteins Leads to Increased Levels of Neuronal Ferritin Heavy Chain, Synaptic Injury, and Deficits in Flexible Attention.

Synaptodendritic pruning and alterations in neurotransmission are the main underlying causes of HIV-associated neurocognitive disorders (HAND). Our studies in humans and nonhuman primates indicated that the protein ferritin heavy chain (FHC) is a critical player in neuronal changes and ensuing cognitive deficit observed in these patients. Here we focus on the effect of HIV proteins and inflammatory cytokines implicated in HAND on neuronal FHC levels, dendritic changes, and neurocognitive behavior. In two well characterized models of HAND (HIV transgenic and gp120-treated rats), we report reductions in spine density and dendritic branches in prefrontal cortex pyramidal neurons compared with age-matched controls. FHC brain levels are elevated in these animals, which also show deficits in reversal learning. Moreover, IL-1β, TNF-α, and HIV gp120 upregulate FHC in rat cortical neurons. However, although the inflammatory cytokines directly altered neuronal FHC, gp120 only caused significant FHC upregulation in neuronal/glial cocultures, suggesting that glia are necessary for sustained elevation of neuronal FHC by the viral protein. Although the envelope protein induced secretion of IL-1β and TNF-α in cocultures, TNF-α blockade did not affect gp120-mediated induction of FHC. Conversely, studies with an IL-1β neutralizing antibody or specific IL-1 receptor antagonist revealed the primary involvement of IL-1β in gp120-induced FHC changes. Furthermore, silencing of neuronal FHC abrogates the effect of gp120 on spines, and spine density correlates negatively with FHC levels or cognitive deficit. These results demonstrate that viral and host components of HIV infection increase brain expression of FHC, leading to cellular and functional changes, and point to IL-1β-targeted strategies for prevention of these alterations. Significance statement: This work demonstrates the key role of the cytokine IL-1β in the regulation of a novel intracellular mediator [i.e., the protein ferritin heavy chain (FHC)] of HIV-induced dendritic damage and the resulting neurocognitive impairment. This is also the first study that systematically investigates dendritic damage in layer II/III prefrontal cortex neurons of two different non-infectious models of HIV-associated neurocognitive disorders (HAND) and reveals a precise correlation of these structural changes with specific biochemical and functional alterations also reported in HIV patients. Overall, these data suggest that targeting the IL-1β-dependent FHC increase may represent a valid strategy for neuroprotective adjuvant therapies in HAND.

Increased neuronal PreP activity reduces Aβ accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model.

Accumulation of amyloid-β (Aβ) in synaptic mitochondria is associated with mitochondrial and synaptic injury. The underlying mechanisms and strategies to eliminate Aβ and rescue mitochondrial and synaptic defects remain elusive. Presequence protease (PreP), a mitochondrial peptidasome, is a novel mitochondrial Aβ degrading enzyme. Here, we demonstrate for the first time that increased expression of active human PreP in cortical neurons attenuates Alzheimer disease's (AD)-like mitochondrial amyloid pathology and synaptic mitochondrial dysfunction, and suppresses mitochondrial oxidative stress. Notably, PreP-overexpressed AD mice show significant reduction in the production of proinflammatory mediators. Accordingly, increased neuronal PreP expression improves learning and memory and synaptic function in vivo AD mice, and alleviates Aβ-mediated reduction of long-term potentiation (LTP). Our results provide in vivo evidence that PreP may play an important role in maintaining mitochondrial integrity and function by clearance and degradation of mitochondrial Aβ along with the improvement in synaptic and behavioral function in AD mouse model. Thus, enhancing PreP activity/expression may be a new therapeutic avenue for treatment of AD.