The effects of enhancing angiotensin converting enzyme in myelomonocytes on ameliorating Alzheimer's-related disease and preserving cognition.

This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein (Aβ), a peptide strongly associated with AD. Previous studies in mice, demonstrated that targeted overexpression of ACE in CD115 myelomonocytic cells (ACE10 models) improved their immune responses to effectively reduce viral and bacterial infection, tumor growth, and atherosclerotic plaque.

Case Report: Early-Onset Behavioral Variant Frontotemporal Dementia in Patient With Retrotransposed Full-Length Transcript of Variant 5.

Frontotemporal dementia (FTD) rarely occurs in individuals under the age of 30, and genetic causes of early-onset FTD are largely unknown. The current report follows a 27 year-old patient with no significant past medical history presenting with two years of progressive changes in behavior, rushed speech, verbal aggression, and social withdrawal. MRI and FDG-PET imaging of the brain revealed changes maximally in the frontal and temporal lobes, which along with the clinical features, are consistent with behavioral variant FTD.

Reaction time and response inhibition in autosomal dominant Alzheimer's disease.

Objective: Subtle deficits in several cognitive domains characterize the neuropsychological profile of preclinical Alzheimer's disease (AD). Assessment of preclinical individuals with genes causing autosomal dominant AD (ADAD) provides a model for prodromal disease. We sought to sensitively evaluate attention and working memory using a computerized battery in non-demented persons carrying ADAD mutations.

Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ Oligomers and Protect Synapses.

Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs.

Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease.

Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-β protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer's-like disease in double-transgenic APPSWE/PS1ΔE9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood.

A novel role for osteopontin in macrophage-mediated amyloid-β clearance in Alzheimer's models.

Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by myelomonocytic cells, is known to regulate immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes achieved through glatiramer acetate (GA) immunization or peripheral blood enrichment with bone marrow (BM)-derived CD115 monocytes (Mo) curbs amyloid β-protein (Aβ) neuropathology and preserves cognitive function in murine models of Alzheimer's disease (ADtg mice). To elucidate the beneficial mechanisms of these immunomodulatory approaches in AD, we focused on the potential role of OPN in macrophage-mediated Aβ clearance.

Aggregation of Chameleon Peptides: Implications of α-Helicity in Fibril Formation.

We investigate the relationship between the inherent secondary structure and aggregation propensity of peptides containing chameleon sequences (i.e., sequences that can adopt either α or β structure depending on context) using a combination of replica exchange molecular dynamics simulations, ion-mobility mass spectrometry, circular dichroism, and transmission electron microscopy.

Amyloid β-Protein Assembly and Alzheimer's Disease: Dodecamers of Aβ42, but Not of Aβ40, Seed Fibril Formation.

Evidence suggests that oligomers of the 42-residue form of the amyloid β-protein (Aβ), Aβ42, play a critical role in the etiology of Alzheimer's disease (AD). Here we use high resolution atomic force microscopy to directly image populations of small oligomers of Aβ42 that occur at the earliest stages of aggregation. We observe features that can be attributed to a monomer and to relatively small oligomers, including dimers, hexamers, and dodecamers.

Amyloid β-Protein C-Terminal Fragments: Formation of Cylindrins and β-Barrels.

In order to evaluate potential therapeutic targets for treatment of amyloidoses such as Alzheimer's disease (AD), it is essential to determine the structures of toxic amyloid oligomers. However, for the amyloid β-protein peptide (Aβ), thought to be the seminal neuropathogenetic agent in AD, its fast aggregation kinetics and the rapid equilibrium dynamics among oligomers of different size pose significant experimental challenges. Here we use ion-mobility mass spectrometry, in combination with electron microscopy, atomic force microscopy, and computational modeling, to test the hypothesis that Aβ peptides can form oligomeric structures resembling cylindrins and β-barrels.

Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease.

Objective: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD).

Methods: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation.

Conformation-dependent oligomers in cerebrospinal fluid of presymptomatic familial Alzheimer's disease mutation carriers.

Background/aims: Oligomerization of amyloid beta (Aβ) is a hypothesized step in the formation of plaques in Alzheimer's disease (AD) but has been difficult to demonstrate in vivo in humans. As persons destined to develop familial AD (FAD) due to fully penetrant autosomal dominant mutations are essentially certain to develop the disease, they provide the opportunity to identify oligomers during the presymptomatic stage of the disease.

Methods: We measured levels of Aβ(42) using a conventional immunoassay and prefibrillar, fibrillar, and annular protofibrillar oligomers using polyclonal conformation-dependent antibodies in the cerebrospinal fluid (CSF) of 7 persons at risk for inheriting FAD mutations.

Cerebrospinal fluid biomarkers and proximity to diagnosis in preclinical familial Alzheimer's disease.

Background/aims: Biological markers of utility in tracking Alzheimer's disease (AD) during the presymptomatic prodromal phase are important for prevention studies. Changes in cerebrospinal fluid (CSF) levels of 42-amino-acid β-amyloid (Aβ(42)), total tau protein (t-tau) and phosphorylated tau at residue 181 (p-tau(181)) during this state are incompletely characterized.

Methods: We measured CSF markers in 13 carriers of familial AD (FAD) mutations that are fully penetrant for causing AD (PSEN1 and APP) and in 5 non-mutation-carrying family members.

Effects of rivastigmine transdermal patch and capsule on aspects of clinical global impression of change in Alzheimer's disease: a retrospective analysis.

Background: The Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale is widely used in Alzheimer trials. It assesses cognition, activities of daily living (ADLs), behavior and global functioning. To advance the understanding of relationships between the ADCS-CGIC and scores from other commonly used tools, this analysis investigated the ability of each domain to measure change.

Integrating ADNI results into Alzheimer's disease drug development programs.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is providing critical new information on biomarkers in cognitively normal elderly, persons with mild cognitive impairment (MCI), and patients with mild Alzheimer's disease (AD). The data provide insights into the progression of the pathology of AD over time, assist in understanding which biomarkers might be most useful in clinical trials, and facilitate development of disease-modifying treatments. ADNI results are intended to support new AD treatment development; this report considers how ADNI information can be integrated in AD drug development programs.

Effects of rivastigmine in Alzheimer's disease patients with and without hallucinations.

Hallucinations in Alzheimer's disease (AD) may indicate greater cortical cholinergic deficits. Rivastigmine has shown larger treatment benefits versus placebo in dementia with Lewy bodies and Parkinson's disease dementia patients with hallucinations. In this retrospective, hypothesis-generating analysis, we investigated whether hallucinations in AD were associated with greater treatment benefits with rivastigmine.

Mary S. Easton Center of Alzheimer's Disease Research at UCLA: advancing the therapeutic imperative.

The Mary S. Easton Center for Alzheimer's Disease Research (UCLA-Easton Alzheimer's Center) is committed to the "therapeutic imperative" and is devoted to finding new treatments for Alzheimer's disease (AD) and to developing technologies (biomarkers) to advance that goal. The UCLA-Easton Alzheimer's Center has a continuum of research and research-related activities including basic/foundational studies of peptide interactions; translational studies in transgenic animals and other animal models of AD; clinical research to define the phenotype of AD, characterize familial AD, develop biomarkers, and advance clinical trials; health services and outcomes research; and active education, dissemination, and recruitment activities.

Rivastigmine transdermal patch skin tolerability: results of a 1-year clinical trial in patients with mild-to-moderate Alzheimer's disease.

Background And Objectives: Transdermal patches provide non-invasive, continuous drug delivery, and offer significant potential advantages over oral treatments. With all transdermal treatments a proportion of patients will experience some form of skin reaction. The rivastigmine patch has been approved for the treatment of mild-to-moderate Alzheimer's disease (AD) since July 2007 in the US.

Defining and labeling disease-modifying treatments for Alzheimer's disease.

Alzheimer's disease (AD) might be treated with symptomatic, neuroprotective, or neurorestorative therapies. Neuroprotective and neurorestorative interventions are disease-modifying therapies. Disease modification can be defined as treatments or interventions that affect the underlying pathophysiology of the disease and have a beneficial outcome on the course of AD.

Current concepts of mild cognitive impairment and their applicability to persons at-risk for familial Alzheimer's disease.

The definition of mild cognitive impairment (MCI) as a precursor for Alzheimer's disease (AD) represented an important step forward in diagnosing the illness in its earliest stage. However, diagnoses based principally on cognitive performance have limitations in that there is variability between centers in which tests are employed and in how they are interpreted. Advances in our understanding of imaging and biochemical changes occurring early in the illness have improved our ability to diagnose AD in this early phase and diagnostic criteria for AD have been proposed recently based on such biomarkers.