Impaired electrical activity of the brain explains the onset of dementia in aging people.

Aging brains that share many cognitive deficits with the early stages of Alzheimer's-type dementias are not caused by toxic protein deposits but by somatic mutations that impair synaptic signaling. These mutant proteins that contribute to neuronal action potentials could be biomarkers of functional defects that offer new approaches to diagnosis and treatment.

digenic mutations of telomere-associated proteins and inflammasomes initiate many chronic human diseases: a hypothesis.

Many age-related human diseases have inflammatory components of uncertain causes. It has been proposed that some may be initiated or sustained by doubly mutated immune cells that have both inappropriately activated inflammasomes and enhanced replicative potential. Genes of cells that express mutant TERT and NLRP3 proteins are presumed to be at increased risk for mutagenesis because they reside in subtelomeric regions of chromatin that are deficient in DNA repair mechanisms.

Gain-of-function somatic mutations contribute to inflammation and blood vessel damage that lead to Alzheimer dementia: a hypothesis.

Amyloid deposits are a characteristic feature of advanced Alzheimer dementia (AD), but whether they initiate the disease or are a consequence of it remains an unsettled question. To explore an alternative pathogenic mechanism, I propose that the triggering events that begin the pathogenic cascade are not amyloid deposits but damaged blood vessels caused by inflammatory reactions that lead to ischemia, amyloid accumulation, axonal degeneration, synaptic loss, and eventually irreversible neuronal cell death. Inflammation and blood vessel damage are well recognized complications of AD, but what causes them and why the cerebral microvasculature is affected have never been adequately addressed.

Alzheimer's disease and CADASIL are heritable, adult-onset dementias that both involve damaged small blood vessels.

This essay explores an alternative pathway to Alzheimer's dementia that focuses on damage to small blood vessels rather than late-stage toxic amyloid deposits as the primary pathogenic mechanism that leads to irreversible dementia. While the end-stage pathology of AD is well known, the pathogenic processes that lead to disease are often assumed to be due to toxic amyloid peptides that act on neurons, leading to neuronal dysfunction and eventually neuronal cell death. Speculations as to what initiates the pathogenic cascade have included toxic abeta peptide aggregates, oxidative damage, and inflammation, but none explain why neurons die.

Alzheimer's disease 2012: the great amyloid gamble.

Alzheimer's disease threatens to become the scourge of the 21st century. Hundreds of millions of aging people throughout the world are at risk, but it is clear that the disease encompasses more than just the natural aging process. Deposits of amyloid β peptides in the brains of demented individuals are a defining feature of the disease, yet two decades of intensive investigation, focusing on reducing or removing amyloid deposits, have failed to produce any meaningful therapeutic interventions.

Alzheimer's dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy.

There is a widely shared view among Alzheimer's disease (AD) investigators that the amyloid hypothesis best describes the pathogenic cascade that leads, ultimately, to neuronal degeneration and irreversible dementia. The most persuasive evidence comes from studies of damaged brains of patients in the late stages of AD and from animal studies that attempt to mimic the hereditary forms of early-onset dementia. Despite this impressive body of knowledge, we still lack the means to either arrest or prevent this horrible contagion.

Requirement for AHNAK1-mediated calcium signaling during T lymphocyte cytolysis.

Cytolytic CD8(+) T cells (CTLs) kill virally infected cells, tumor cells, or other potentially autoreactive T cells in a calcium-dependent manner. To date, the molecular mechanism that leads to calcium intake during CTL differentiation and function has remained unresolved. We demonstrate that desmoyokin (AHNAK1) is expressed in mature CTLs, but not in naive CD8(+) T cells, and is critical for calcium entry required for their proper function during immune response.

A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation.

Engagement of the T cell antigen receptor (TCR) during antigen presentation initiates a coordinated action of a large number of signaling proteins and ion channels. AHNAK1 is a scaffold protein, highly expressed by CD4+ T cells, and is a critical component for calcium signaling. We showed that AHNAK1-deficient mice were highly susceptible to Leishmania major infection.

The relevance of research on red cell membranes to the understanding of complex human disease: a personal perspective.

Molecular analysis in the service of research on human disease has finally come of age, as the chapters within this volume testify. Many technical advances, among them the development of recombinant DNA and its many applications, opened the way to study cells and processes that were unapproachable in the 1960s, when I first began my research career. The state of molecular biological studies at that time limited studies of human cell membrane proteins to experimental material most available and accessible, making the human erythrocyte membrane the favored target.

An alternative interpretation of the amyloid Abeta hypothesis with regard to the pathogenesis of Alzheimer's disease.

Alzheimer's disease is a complex neurodegenerative process that is believed to be due to the accumulation of short, hydrophobic peptides derived from amyloid precursor proteins by proteolytic cleavage. It is widely believed that these Abeta peptides are secreted into the extracellular spaces of the CNS, where they assemble into toxic oligomers that kill neurons and eventually form deposits of senile plaques. This essay explores the possibility that a fraction of these Abeta peptides never leave the membrane lipid bilayer after they are generated, but instead exert their toxic effects by competing with and compromising the functions of intramembranous segments of membrane-bound proteins that serve many critical functions.

The AHNAKs are a class of giant propeller-like proteins that associate with calcium channel proteins of cardiomyocytes and other cells.

To explore the function of the giant AHNAK molecule, first described in 1992 [Shtivelman, E., Cohen, F. E.