Altered hippocampal doublecortin expression in Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor and non-motor symptoms. Motor symptoms include bradykinesia, resting tremors, muscular rigidity, and postural instability, while non-motor symptoms include cognitive impairments, mood disturbances, sleep disturbances, autonomic dysfunction, and sensory abnormalities. Some of these symptoms may be influenced by the proper hippocampus functioning, including adult neurogenesis.

Regional AT-8 reactive tau species correlate with intracellular Aβ levels in cases of low AD neuropathologic change.

The amyloid cascade hypothesis states that Aβ aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble Aβ and tau species in the revised amyloid cascade hypothesis.

Nuclear alpha-synuclein is present in the human brain and is modified in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is pathologically defined by the cytoplasmic accumulation of alpha-synuclein (aSyn) within neurons in the brain. Predominately pre-synaptic, aSyn has been reported in various subcellular compartments in experimental models. Indeed, nuclear alpha-synuclein (aSyn) is evident in many models, the dysregulation of which is associated with altered DNA integrity, transcription and nuclear homeostasis.

Therapeutic Targeting of Rab GTPases: Relevance for Alzheimer's Disease.

Rab GTPases (Rabs) are small proteins that play crucial roles in vesicle transport and membrane trafficking. Owing to their widespread functions in several steps of vesicle trafficking, Rabs have been implicated in the pathogenesis of several disorders, including cancer, diabetes, and multiple neurodegenerative diseases. As treatments for neurodegenerative conditions are currently rather limited, the identification and validation of novel therapeutic targets, such as Rabs, is of great importance.

Prion-like α-synuclein pathology in the brain of infants with Krabbe disease.

Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene that causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (n = 4) compared to infant controls (n = 4) and identified widespread accumulations of α-synuclein.

Dysfunction of RAB39B-Mediated Vesicular Trafficking in Lewy Body Diseases.

Intracellular vesicular trafficking is essential for neuronal development, function, and homeostasis and serves to process, direct, and sort proteins, lipids, and other cargo throughout the cell. This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death.

RAB39B is redistributed in dementia with Lewy bodies and is sequestered within aβ plaques and Lewy bodies.

Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X-linked Parkinson's disease (PD). Physiologically, RAB39B is localized to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha-Synuclein (aSyn) homeostasis and the inhibition of its aggregation. Despite evidence linking RAB39B to neurodegeneration, the involvement of the protein in idiopathic neurodegenerative diseases remains undetermined.

Synaptic Loss, ER Stress and Neuro-Inflammation Emerge Late in the Lateral Temporal Cortex and Associate with Progressive Tau Pathology in Alzheimer's Disease.

The complex multifactorial nature of AD pathogenesis has been highlighted by evidence implicating additional neurodegenerative mechanisms, beyond that of amyloid-β (Aβ) and tau. To provide insight into cause and effect, we here investigated the temporal profile and associations of pathological changes in synaptic, endoplasmic reticulum (ER) stress and neuro-inflammatory markers. Quantifications were established via immunoblot and immunohistochemistry protocols in post-mortem lateral temporal cortex (n = 46).

Knock-in of Mutated hTAU Causes Insulin Resistance, Inflammation and Proteostasis Disturbance in a Mouse Model of Frontotemporal Dementia.

Diabetes and obesity have been implicated as risk factors for dementia. However, metabolic mechanisms and associated signalling pathways have not been investigated in detail in frontotemporal dementia. We therefore here characterised physiological, behavioural and molecular phenotypes of 3- and 8-month-old male tau knock-in (PLB2) vs wild-type (PLB) mice.

Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies.

Alpha-synuclein (aSyn) accumulates in intracellular inclusions in synucleinopathies, but the molecular mechanisms leading to disease are unclear. We identify the 10 kDa heat shock protein (HSP10) as a mediator of aSyn-induced mitochondrial impairments in striatal synaptosomes. We find an age-associated increase in the cytosolic levels of HSP10, and a concomitant decrease in the mitochondrial levels, in aSyn transgenic mice.

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies.

Alpha-synuclein (α-Syn) is a central player in Parkinson's disease (PD) and in a spectrum of neurodegenerative diseases collectively known as synucleinopathies. The protein was first associated with PD just over 20 years ago, when it was found to (i) be a major component of Lewy bodies and (ii) to be also associated with familial forms of PD. The characterization of α-Syn pathology has been achieved through postmortem studies of human brains.

Dementia with Lewy bodies: an update and outlook.

Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson's disease (PD). Extrapyramidal motor features characteristic of PD, are common in DLB patients, but are not essential for the clinical diagnosis of DLB.

Distinctive temporal profiles of detergent-soluble and -insoluble tau and Aβ species in human Alzheimer's disease.

Alzheimer's disease (AD) pathology relevant proteins tau and beta-amyloid (Aβ) exist as an array of post-translationally modified and conformationally altered species with varying abundance, solubility and toxicity. Insoluble neurofibrillary tau tangles and Aβ plaques are end-stage AD hallmarks, yet may carry less disease significance compared to soluble species. At present, it is unclear how soluble and insoluble tau and Aβ relate to each other as well as to disease progression.

Alzheimer's disease pathology and the unfolded protein response: prospective pathways and therapeutic targets.

Many vital interdependent cellular functions including proteostasis, lipogenesis and Ca homeostasis are executed by the endoplasmic reticulum (ER). Exogenous insults can impair ER performance: this must be rapidly corrected or cell death will ensue. Protective adaptations can boost the functional capacity of the ER and form the basis of the unfolded protein response (UPR).

Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer's disease and track disease progression and cognitive decline.

Post-mortem investigations of human Alzheimer's disease (AD) have largely failed to provide unequivocal evidence in support of the original amyloid cascade hypothesis, which postulated deposition of β-amyloid (Aβ) aggregates to be the cause of a demented state as well as inductive to tau neurofibrillary tangles (NFTs). Conflicting evidence suggests, however, that Aβ plaques and NFTs, albeit to a lesser extent, are present in a substantial subset of non-demented individuals. Hence, a range of soluble tau and Aβ species has more recently been implicated as the disease-relevant toxic entities.

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology.

Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTauP301L+R406W) knock-in mouse was generated out of the previously characterised PLB1Triple mouse, and named PLB2Tau.

Age-dependent changes in hippocampal synaptic transmission and plasticity in the PLB1Triple Alzheimer mouse.

Several genetically engineered models exist that mimic aspects of the pathological and cognitive hallmarks of Alzheimer's disease (AD). Here we report on a novel mouse model generated by targeted knock-in of transgenes containing mutated human amyloid precursor protein (APP) and microtubule-associated protein tau genes, inserted into the HPRT locus and controlled by the CaMKIIα regulatory element. These mice were crossed with an asymptomatic presenilin1A246E overexpressing line to generate PLB1Triple mice.

Store-operated Ca2+ entry in hippocampal neurons: Regulation by protein tyrosine phosphatase PTP1B.

Store operated Ca(2+) entry (SOCE) replenishes intracellular Ca(2+) stores and activates a number of intracellular signalling pathways. Whilst several molecular components forming store operated Ca(2+) channels (SOCC) have been identified, their modulation in neurons remains poorly understood. Here, we extend on our previous findings and show that neuronal SOCE is modulated by tyrosine phosphorylation.

Intracellular Ca2+ stores modulate SOCCs and NMDA receptors via tyrosine kinases in rat hippocampal neurons.

The regulation of intracellular Ca(2+) signalling by phosphorylation processes remains poorly defined, particularly with regards to tyrosine phosphorylation. Evidence from non-excitable cells implicates tyrosine phosphorylation in the activation of so-called store-operated Ca(2+) channels (SOCCs), but their involvement in neuronal Ca(2+) signalling is still elusive. In the present study, we determined the role of protein tyrosine kinases (PTKs) and tyrosine phosphatases (PTPs) in the coupling between intracellular Ca(2+) stores and SOCCs in neonatal rat hippocampal neurons by Fura-2 Ca(2+) imaging.

Modulation of hippocampal calcium signalling and plasticity by serine/threonine protein phosphatases.

Kinases and phosphatases act antagonistically to maintain physiological phosphorylation/dephosphorylation at numerous intracellular sites critical for neuronal signalling. In this study, it was found that inhibition of serine/threonine phosphatases by exposure of hippocampal slices to okadaic acid (OA) or cantharidin (CA; 100 nmol/L) for 2 h resulted in reduced basal synaptic transmission and blocked the induction of synaptic plasticity in the form of long-term potentiation as determined by electrophysiological analysis. Fura-2 Ca(2+) imaging revealed a bidirectional modulation of N-methyl-D-aspartate (NMDA) -mediated Ca(2+) responses and reduced KCl-mediated Ca(2+) responses in neonatal cultured hippocampal neurons after phosphatase inhibition.

A comparative study of the actions of alkylpyridinium salts from a marine sponge and related synthetic compounds in rat cultured hippocampal neurones.

Background: Polymeric alkylpyridinium salts (poly-APS), are chemical defences produced by marine sponges including Reniera sarai. Poly-APS have previously been shown to effectively deliver macromolecules into cells. The efficiency of this closely follows the ability of poly-APS to form transient pores in membranes, providing strong support for a pore-based delivery mechanism.