Chronic Lithium Treatment Increases Telomere Length in Parietal Cortex and Hippocampus of Triple-Transgenic Alzheimer's Disease Mice.

Telomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer's disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system.

Stereological investigation of the CA1 pyramidal cell layer in untreated and lithium-treated 3xTg-AD and wild-type mice.

Pyramidal neuron loss in the hippocampal CA1 region is a very early hallmark of Alzheimer disease (AD). Lithium might be a therapeutic strategy for AD due to its neuroprotective and neurotrophic properties. This study used modern stereological techniques to investigate possible CA1 pyramidal neuron loss in 11-month-old triple transgenic AD (3xTg-AD) mice, and also the effects of therapeutic and subtherapeutic lithium doses on the number and density of CA1 pyramidal neurons and volume of CA1 pyramidal layer in 3xTg-AD and wild-type mice treated from 3 to 11 months of age.

Long-Term Lithium Treatment Increases cPLA₂ and iPLA₂ Activity in Cultured Cortical and Hippocampal Neurons.

Background: Experimental evidence supports the neuroprotective properties of lithium, with implications for the treatment and prevention of dementia and other neurodegenerative disorders. Lithium modulates critical intracellular pathways related to neurotrophic support, inflammatory response, autophagy and apoptosis. There is additional evidence indicating that lithium may also affect membrane homeostasis.

Chronic inhibition of brain phospholipase A2 in adult rats impairs the survival of newborn mature neurons in the hippocampus.

Adult neurogenesis occurs in the hippocampal dentate gyrus (DG) and lateral ventricles, and includes cell proliferation and neuronal differentiation, maturation and survival. In vitro studies suggest a role for phospholipase A2 (PLA2) in neuronal differentiation/maturation and survival. This study aimed to investigate the effect of in vivo chronic inhibition of brain PLA2 in adult rats on the number of newborn mature neurons in the DG.

Synergistic and additive effects of enriched environment and lithium on the generation of new cells in adult mouse hippocampus.

Hippocampal atrophy is reported in several neuropathological disorders. The hippocampal dentate gyrus (DG) is a brain region where adult neurogenesis constitutively occurs. There are some reports suggesting the ability of endogenous neurogenesis to initiate neuronal repair in the hippocampus in response to neuropathological conditions, but its capacity to compensate for neuronal loss is limited.

Low platelet iPLA₂ activity predicts conversion from mild cognitive impairment to Alzheimer's disease: a 4-year follow-up study.

Reduced phospholipase A₂ (PLA₂) activity has been reported in the brain and in blood cells of patients with Alzheimer's disease (AD). Individuals with mild cognitive impairment (MCI) are at increased risk of developing AD. In the present study, we determined the activity of distinct PLA₂ subgroups (iPLA₂, sPLA₂ and cPLA₂) in older adults with MCI as compared to patients with mild dementia due to AD and to cognitively healthy controls.

Increased cell proliferation in the rat anterior cingulate cortex following neonatal hypoxia: relevance to schizophrenia.

As a consequence of obstetric complications, neonatal hypoxia has been discussed as an environmental factor in the pathophysiology of schizophrenia. However, the biological consequences of hypoxia are unclear. The neurodevelopmental hypothesis of schizophrenia suggests that the onset of abnormal brain development and neuropathology occurs perinatally, whereas symptoms of the disease appear in early adulthood.

Insights into Alzheimer disease pathogenesis from studies in transgenic animal models.

Alzheimer disease is the most common cause of dementia among the elderly, accounting for ~60-70% of all cases of dementia. The neuropathological hallmarks of Alzheimer disease are senile plaques (mainly containing p-amyloid peptide derived from amyloid precursor protein) and neurofibrillary tangles (containing hyperphosphorylated Tau protein), along with neuronal loss. At present there is no effective treatment for Alzheimer disease.

Inhibition of phospholipase A₂ in rat brain modifies different membrane fluidity parameters in opposite ways.

Fluidity is an important neuronal membrane property and it is influenced by the concentration of polyunsaturated fatty acids (PUFAs) in membrane phospholipids. Phospholipase A(2) (PLA(2)) is a key enzyme in membrane phospholipid metabolism, generating free PUFAs. In Alzheimer disease (AD), reduced PLA(2) activity, specifically of calcium-dependent cytosolic PLA(2) (cPLA(2)) and calcium-independent intracellular PLA(2) (iPLA(2)), and phospholipid metabolism was reported in the frontal cortex and hippocampus.

Inhibition of phospholipase A2 in rat brain decreases the levels of total Tau protein.

The microtubule-associated protein Tau promotes the assembly and stability of microtubules in neuronal cells. Six Tau isoforms are expressed in adult human brain. All six isoforms become abnormally hyperphosphorylated and form neurofibrillary tangles in Alzheimer disease (AD) brains.

Differential roles of phospholipases A2 in neuronal death and neurogenesis: implications for Alzheimer disease.

The involvement of phospholipase A(2) (PLA(2)) in Alzheimer disease (AD) was first investigated nearly 15 years ago. Over the years, several PLA(2) isoforms have been detected in brain tissue: calcium-dependent secreted PLA(2) or sPLA(2) (IIA, IIC, IIE, V, X, and XII), calcium-dependent cytosolic PLA(2) or cPLA(2) (IVA, IVB, and IVC), and calcium-independent PLA(2) or iPLA(2) (VIA and VIB). Additionally, numerous in vivo and in vitro studies have suggested the role of different brain PLA(2) in both physiological and pathological events.

Inhibition of phospholipase A2 increases tau phosphorylation at Ser214 in embryonic rat hippocampal neurons.

Background: Arachidonic acid is released from cellular membranes by the action of phospholipase A(2) (PLA(2)) and is implicated in microtubule-associated protein Tau phosphorylation. Tau hyperphosphorylation affects its ability to stabilize microtubules.

Objective: To determine the effect of PLA(2) inhibition on the phosphorylation state of Tau phosphoepitopes in primary cultures of hippocampal neurons.

Strategies to promote differentiation of newborn neurons into mature functional cells in Alzheimer brain.

Adult neurogenesis occurs in the subgranular zone (SGZ) and subventricular zone (SVZ). New SGZ neurons migrate into the granule cell layer of the dentate gyrus (DG). New SVZ neurons seem to enter the association neocortex and entorhinal cortex besides the olfactory bulb.

Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease.

Rationale: Alzheimer disease (AD) is the leading cause of dementia in the elderly and has no known cure. Evidence suggests that reduced activity of specific subtypes of intracellular phospholipases A2 (cPLA2 and iPLA2) is an early event in AD and may contribute to memory impairment and neuropathology in the disease.

Objective: The objective of this study was to review the literature focusing on the therapeutic role of PLA2 stimulation by cognitive training and positive modulators, or of supplementation with arachidonic acid (PLA2 product) in facilitating memory function and synaptic transmission and plasticity in either research animals or human subjects.

Stereologic investigation of the posterior part of the hippocampus in schizophrenia.

Structural magnetic resonance imaging and postmortem studies showed volume loss in the hippocampus in schizophrenia. The noted tissue reduction in the posterior section suggests that some cellular subfractions within this structure might be reduced in schizophrenia. To address this, we investigated numbers and densities of neurons, oligodendrocytes and astrocytes in the posterior hippocampal subregions in postmortem brains from ten patients with schizophrenia and ten matched controls using design-based stereology performed on Nissl-stained sections.

Cholinergic and glutamatergic alterations beginning at the early stages of Alzheimer disease: participation of the phospholipase A2 enzyme.

Rationale: Alzheimer disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia in the elderly. A combination of cholinergic and glutamatergic dysfunction appears to underlie the symptomatology of AD, and thus, treatment strategies should address impairments in both systems. Evidence suggests the involvement of phospholipase A(2) (PLA(2)) enzyme in memory impairment and neurodegeneration in AD via actions on both cholinergic and glutamatergic systems.

Inhibition of calcium-independent phospholipase A2 activity in rat hippocampus impairs acquisition of short- and long-term memory.

Rationale: Phospholipase A(2) (PLA(2)) is a family of enzymes that cleave membrane phospholipids generating important lipid mediators in signal transduction. In rat hippocampal slices, both intracellular cytosolic Ca(2+)-dependent PLA(2) (cPLA(2)) and Ca(2+)-independent PLA(2) (iPLA(2)) have been implicated in mechanisms of synaptic plasticity underlying memory processes. In mice, intraperitoneal injections of a selective iPLA(2) inhibitor impaired spatial learning.