Pharmacological intervention in a transgenic mouse model improves Alzheimer's-associated pathological phenotype: Involvement of proteasome activation.

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by a progressive decline in a variety of cognitive and non-cognitive functions. The amyloid beta protein cascade hypothesis places the formation of amyloid beta protein aggregates on the first position in the complex pathological cascade leading to neurodegeneration, and therefore AD might be considered to be a protein-misfolding disease. The Ubiquitin Proteasome System (UPS), being the primary protein degradation mechanism with a fundamental role in the maintenance of proteostasis, has been identified as a putative therapeutic target to delay and/or to decelerate the progression of neurodegenerative disorders that are characterized by accumulated/aggregated proteins.

Dietary Restriction and Oxidative Stress: Friends or Enemies?

It is well established that lifestyle and dietary habits have a tremendous impact on life span, the rate of aging, and the onset/progression of age-related diseases. Specifically, dietary restriction (DR) and other healthy dietary patterns are usually accompanied by physical activity and differ from Western diet that is rich in fat and sugars. Moreover, as the generation of reactive oxidative species is the major causative factor of aging, while DR could modify the level of oxidative stress, it has been proposed that DR increases both survival and longevity.

Frailty index and phenotype frailty score: Sex- and age-related differences in 5XFAD transgenic mouse model of Alzheimer's disease.

Alzheimer's disease patients (AD), as well as AD transgenic mice, are characterized by increased frailty. Furthermore, the assessment of frailty status represents a feasible approach for detecting individuals prone to develop more severe form of AD and for measuring the outcome of existing and putative AD therapeutics. The 5xFAD mouse is one of the widely used transgenic animal models of AD, but frailty in this model is scantly investigated.

Limited daily feeding and intermittent feeding have different effects on regional brain energy homeostasis during aging.

Albeit aging is an inevitable process, the rate of aging is susceptible to modifications. Dietary restriction (DR) is a vigorous nongenetic and nonpharmacological intervention that is known to delay aging and increase healthspan in diverse species. This study aimed to compare the impact of different restricting feeding regimes such as limited daily feeding (LDF, 60% AL) and intermittent feeding (IF) on brain energy homeostasis during aging.

Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord.

Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease. The presence of myelin lipid debris was seen only at the peak of EAE in demyelination loci being efficiently removed during the recovery period.

Loss of Cathepsin B and L Leads to Lysosomal Dysfunction, NPC-Like Cholesterol Sequestration and Accumulation of the Key Alzheimer's Proteins.

Proper function of lysosomes is particularly important in neurons, as they cannot dilute accumulated toxic molecules and aggregates by cell division. Thus, impairment of lysosomal function plays an important role in neuronal degeneration and in the pathogenesis of numerous neurodegenerative diseases. In this work we analyzed how inhibition and/or loss of the major lysosomal proteases, the cysteine cathepsins B and L (CtsB/L), affects lysosomal function, cholesterol metabolism and degradation of the key Alzheimer's disease (AD) proteins.

Interventions for age-related diseases: Shifting the paradigm.

Over 60% of people aged over 65 are affected by multiple morbidities, which are more difficult to treat, generate increased healthcare costs and lead to poor quality of life compared to individual diseases. With the number of older people steadily increasing this presents a societal challenge. Age is the major risk factor for age-related diseases and recent research developments have led to the proposal that pharmacological interventions targeting common mechanisms of ageing may be able to delay the onset of multimorbidity.

Long-term dietary restriction differentially affects the expression of BDNF and its receptors in the cortex and hippocampus of middle-aged and aged male rats.

Dietary restriction (DR) exerts significant beneficial effects in terms of aging and age-related diseases in many organisms including humans. The present study aimed to examine the influence of long-term DR on the BDNF system at the transcriptional and translational levels in the cortex and hippocampus of middle-aged (12-month-old) and aged (24-month-old) male Wistar rats. The obtained results revealed that the DR upregulated the expression of exon-specific BDNF transcripts in both regions, followed by elevated levels of mBDNF only in the cortex in middle-aged animals.

Cholesterol metabolism changes under long-term dietary restrictions while the cholesterol homeostasis remains unaffected in the cortex and hippocampus of aging rats.

Maintaining cholesterol homeostasis in the brain is vital for its proper functioning. While it is well documented that dietary restriction modulates the metabolism of cholesterol peripherally, little is known as to how it can affect cholesterol metabolism in the brain. The present study was designed to elucidate the impact of long-term dietary restriction on brain cholesterol metabolism.

The effects of dietary restriction and aging on amyloid precursor protein and presenilin-1 mRNA and protein expression in rat brain.

The objective of this study was to examine the effects of aging and long-term dietary restriction (DR) on the level of amyloid precursor protein (APP) and presenilin-1 (PS-1), proteins that are critically involved in Alzheimer's disease. Changes in mRNA and protein expression were assessed by real-time PCR and western blot analysis during aging and long-term DR in the cortex and hippocampus of 6-, 12-, 18-, and 24-month-old rats. Prominent regional changes in expression were observed in response to aging and DR.

Aging induces tissue-specific changes in cholesterol metabolism in rat brain and liver.

Disturbance of cholesterol homeostasis in the brain is coupled to age-related brain dysfunction. In the present work, we studied the relationship between aging and cholesterol metabolism in two brain regions, the cortex and hippocampus, as well as in the sera and liver of 6-, 12-, 18- and 24-month-old male Wistar rats. Using gas chromatography-mass spectrometry, we undertook a comparative analysis of the concentrations of cholesterol, its precursors and metabolites, as well as dietary-derived phytosterols.

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat.

Neurotrophins are established molecular mediators of neuronal plasticity in the adult brain. We analyzed the impact of aging on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) protein isoforms, their receptors, and on the expression patterns of multiple 5' exon-specific BDNF transcripts in the rat cortex and hippocampus throughout the life span of the rat (6, 12, 18, and 24 months of age). ProNGF was increased during aging in both structures.

Brain injury induces cholesterol 24-hydroxylase (Cyp46) expression in glial cells in a time-dependent manner.

Maintaining the cholesterol homeostasis is essential for normal CNS functioning. The enzyme responsible for elimination of cholesterol excess from the brain is cholesterol 24-hydroxylase (Cyp46). Since cholesterol homeostasis is disrupted following brain injury, in this study we examined the effect of right sensorimotor cortex suction ablation on cellular and temporal pattern of Cyp46 expression in the rat brain.

Long-term dietary restriction modulates the level of presynaptic proteins in the cortex and hippocampus of the aging rat.

Brain aging is related to the numerous structural and functional changes including decreased synaptic plasticity. The beneficial effects of dietary restriction (DR) are well known but insufficiently investigated at the level of plasticity-related markers. Therefore, the aim of this study was to examine the expression profiles of proteins structurally and functionally related to synapses-growth-associated protein 43 (GAP-43), synaptophysin (SPH) and alpha-synuclein (alpha-Syn), in the course of aging and in response to long-term DR.

Expression of cholesterol homeostasis genes in the brain of the male rat is affected by age and dietary restriction.

Expression profiles of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), apolipoprotein E (ApoE) and cholesterol 24S-hydroxylase (CYP46), proteins involved in cholesterol biosynthesis, transport and excretion from the CNS, were analyzed in the rat cortex, hippocampus and cerebellum as a function of aging (6–24 months) and in response to long-term dietary restriction (DR). Age-related increases for all three mRNAs were observed, with the highest induction found for Cyp46 in the cortex and hippocampus of 24-month-old animals. DR maintained stable levels of Cyp46, HMGR, and ApoE mRNAs during aging, exhibiting an attenuating effect on age-related changes through specific temporal and regional pattern.