Treating Alzheimer's Disease: Focusing on Neurodegenerative Consequences.

Neurodegenerative disorders involve progressive dysfunction and loss of synapses and neurons and brain atrophy, slowly declining memories and cognitive skills, throughout a long process. Alzheimer's disease (AD), the leading neurodegenerative disorder, suffers from a lack of effective therapeutic drugs. Decades of efforts targeting its pathologic hallmarks, amyloid plaques and neurofibrillary tangles, in clinical trials have produced therapeutics with marginal benefits that lack meaningful clinical improvements in cognition.

Alzheimer's therapeutic development: shifting neurodegeneration to neuroregeneration.

Alzheimer's disease (AD), similar to AD-related dementias, is characterized by impaired/lost neuronal structures and functions due to a long progression of neurodegeneration. Derailed endogenous signal pathways and disease processes have critical roles in neurodegeneration and are pharmacological targets in inducing neuroregeneration. Pharmacologically switching/shifting the brain status from neurodegeneration to neuroregeneration is emerging as a new therapeutic concept, one that is not only achievable, but also essential for effective therapy for AD.

Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial.

Background: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies.

Objective: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing.

Methods: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints.

The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, characterized by a progressive depletion of upper and lower motor neurons (MNs) in the brain and spinal cord. The aberrant regulation of several PKC-mediated signal transduction pathways in ALS has been characterized so far, describing either impaired expression or altered activity of single PKC isozymes (α, β, ζ and δ). Here, we detailed the distribution and cellular localization of the ε-isozyme of protein kinase C (PKCε) in human postmortem motor cortex specimens and reported a significant decrease in both PKCε mRNA () and protein immunoreactivity in a subset of sporadic ALS patients.

Morphometric imaging biomarker identifies Alzheimer's disease even among mixed dementia patients.

A definitive diagnosis of Alzheimer's disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin fibroblasts, was used in a double-blind, allcomers (ages 55-90) trial of 3 patient cohorts: AD dementia patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21-all autopsy or genetically confirmed; and non-demented control (AHC) patients N = 27. Fibroblasts cells isolated from 3-mm skin punch biopsies were cultured on a 3-D Matrigel matrix with movement dynamics quantified by image analysis.

PKCε Activation Restores Loss of PKCε, Manganese Superoxide Dismutase, Vascular Endothelial Growth Factor, and Microvessels in Aged and Alzheimer's Disease Hippocampus.

Vascular endothelial dysfunction and capillary loss are currently considered to be a primary phenotype of normal human aging and Alzheimer's disease (AD). Activation of protein kinase C (PKCε) improves several molecular, cellular, physiological, and behavioral endpoints, yet it is not known whether a loss of PKCε activity occurs in the microvascular endothelium in aged and AD hippocampi, whether this loss contributes to microvascular change, or whether activation of PKCε protects against microvascular damage, an early change that induces age-associated memory defect and AD. We investigated the effect of the PKCε activation on microvascular loss in the hippocampus, important for memory storage.

Bryostatin Placebo-Controlled Trials Indicate Cognitive Restoration Above Baseline for Advanced Alzheimer's Disease in the Absence of Memantine1.

Background: In pre-clinical studies of Alzheimer's disease (AD) transgenic mice, bryostatin restored synaptic connections, prevented neuronal death, reduced amyloid plaques, and reduced neurofibrillary tangles.

Objective: Within pre-specified cohorts of advanced AD patients in two double-blind placebo-controlled bryostatin Phase II trials, to conduct exploratory statistical analyses of patients with identical conditions of enrollment and treatment.

Methods: Severe Impairment Battery (SIB) scores above baseline at 5, 9, and 13 weeks were analyzed initially in the complete cases, with multiple imputation methods based on an iterative Markov chain Monte Carlo algorithm used for missing SIB scores.

Neuro-regeneration Therapeutic for Alzheimer's Dementia: Perspectives on Neurotrophic Activity.

Alzheimer's disease (AD), the leading disorder of memory impairment in our aging population, is increasing at an alarming rate. AD is currently identified by three 'gold standard criteria': (i) dementia in life, (ii) amyloid plaques at autopsy, and (iii) neurofibrillary tangles at autopsy. Several autopsy studies have indicated that dementia in life is a consequence of lost synaptic networks in the brain, while many clinical trials targeting neurotoxic amyloid beta (Aβ) have consistently failed to produce therapeutic effects on memory function in AD patients.

Plants Neither Possess nor Require Consciousness.

In claiming that plants have consciousness, 'plant neurobiologists' have consistently glossed over the remarkable degree of structural and functional complexity that the brain had to evolve for consciousness to emerge. Here, we outline a new hypothesis proposed by Feinberg and Mallat for the evolution of consciousness in animals. Based on a survey of the brain anatomy, functional complexity, and behaviors of a broad spectrum of animals, criteria were established for the emergence of consciousness.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Assessing Safety, Tolerability, and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease.

Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau.

Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer's disease (AD) patients.

Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.

Loss in PKC Epsilon Causes Downregulation of MnSOD and BDNF Expression in Neurons of Alzheimer's Disease Hippocampus.

Oxidative stress and amyloid-β (Aβ) oligomers have been implicated in Alzheimer's disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKCɛ). We investigated the reciprocal interaction among oxidative stress, Aβ, and PKCɛ levels and subsequent PKCɛ-dependent MnSOD and BDNF expression in hippocampal pyramidal neurons.

Bryostatin and its synthetic analog, picolog rescue dermal fibroblasts from prolonged stress and contribute to survival and rejuvenation of human skin equivalents.

Skin health is associated with the day-to-day activity of fibroblasts. The primary function of fibroblasts is to synthesize structural proteins, such as collagen, extracellular matrix proteins, and other proteins that support the structural integrity of the skin and are associated with younger, firmer, and more elastic skin that is better able to resist and recover from injury. At sub-nanomolar concentrations (0.

ApoE isoforms differentially regulates cleavage and secretion of BDNF.

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for sporadic or late onset Alzheimer's disease (AD). Brain-derived neurotrophic factor (BDNF) is decreased by 3 to 4-fold in the brains of AD patients at autopsy. ApoE4 mice also have reduced BDNF levels.

Bryostatin Effects on Cognitive Function and PKCɛ in Alzheimer's Disease Phase IIa and Expanded Access Trials.

Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.

Effects of chronic bryostatin-1 on treatment-resistant depression in rats.

Despite over a half-century's intensive research worldwide, the currently available antidepressants remain sub-optimal. Therapeutic options for treatment-resistant depression, for instance, are rather limited. Here, we found that rats exhibited a lasting treatment-resistant depressive immobility in response to open space swim test at a high intensity of induction.

Inhibition of coactivator-associated arginine methyltransferase 1 modulates dendritic arborization and spine maturation of cultured hippocampal neurons.

An improved understanding of the molecular mechanisms in synapse formation provides insight into both learning and memory and the etiology of neurodegenerative disorders. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein methyltransferase that negatively regulates synaptic gene expression and inhibits neuronal differentiation. Despite its regulatory function in neurons, little is known about the CARM1 cellular location and its role in dendritic maturation and synapse formation.

Protein Kinase Cϵ (PKCϵ) Promotes Synaptogenesis through Membrane Accumulation of the Postsynaptic Density Protein PSD-95.

Protein kinase Cϵ (PKCϵ) promotes synaptic maturation and synaptogenesis via activation of synaptic growth factors such as BDNF, NGF, and IGF. However, many of the detailed mechanisms by which PKCϵ induces synaptogenesis are not fully understood. Accumulation of PSD-95 to the postsynaptic density (PSD) is known to lead to synaptic maturation and strengthening of excitatory synapses.

Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice.

Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of thefragile X mental retardation 1gene product, fragile X mental retardation protein. Fragile X mental retardation protein is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, and FXS is a disorder that currently has no effective therapeutics.

Alzheimer's Disease Cerebrospinal Fluid and Neuroimaging Biomarkers: Diagnostic Accuracy and Relationship to Drug Efficacy.

Widely researched Alzheimer's disease (AD) biomarkers include in vivo brain imaging with PET and MRI, imaging of amyloid plaques, and biochemical assays of Aβ 1 - 42, total tau, and phosphorylated tau (p-tau-181) in cerebrospinal fluid (CSF). In this review, we critically evaluate these biomarkers and discuss their clinical utility for the differential diagnosis of AD. Current AD biomarker tests are either highly invasive (requiring CSF collection) or expensive and labor-intensive (neuroimaging), making them unsuitable for use in the primary care, clinical office-based setting, or to assess drug efficacy in clinical trials.

Bryostatin extends tPA time window to 6 h following middle cerebral artery occlusion in aged female rats.

Blood-brain barrier (BBB) disruption and hemorrhagic transformation (HT) following ischemic/reperfusion injury contributes to post-stroke morbidity and mortality. Bryostatin, a potent protein kinase C (PKC) modulator, has shown promise in treating neurological injury. In the present study, we tested the hypothesis that administration of bryostatin would reduce BBB disruption and HT following acute ischemic stroke; thus, prolonging the time window for administering recombinant tissue plasminogen activator (r-tPA).

ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation.

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for several neurodegenerative disorders, including Alzheimer's disease (AD). Epigenetic dysregulation, including aberrations in histone acetylation, is also associated with AD. We show here for the first time that ApoE4 increases nuclear translocation of histone deacetylases (HDACs) in human neurons, thereby reducing BDNF expression, whereas ApoE3 increases histone 3 acetylation and upregulates BDNF expression.

Towards universal therapeutics for memory disorders.

Evidence is accumulating that many memory disorders, including those due to neurodegenerative diseases, traumatic brain injury (TBI), vascular disease, or abnormal brain development, share common features of memory-related pathology. Structural and functional deficits of synapses are at the core of the underlying pathophysiology, constituting a critical point of convergence in memory disorders. Memory therapeutics that target synaptic loss and dysfunction - that is, to slow, halt, or reverse progression of the disorders at the level of synapses, via synaptogenic molecular cascades such as those of protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) - possess universal therapeutic value for many forms of memory disorder.

Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia.

Background: Early onset dementias have variable clinical presentations and are often difficult to diagnose. We established a family pedigree that demonstrated consistent recurrence of very early onset dementia in successive generations.

Objective And Method: In order to refine the diagnosis in this family, we sequenced the exomes of two affected family members and relied on discrete filtering to identify disease genes and the corresponding causal variants.