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.

De novo 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. Expanded clones of proinflammatory cells can occur throughout one's lifetime and could represent an alternative explanation for some forms of pathologic scarring that are now attributed to truncated telomeres.-Marchesi, V. T. De novo digenic mutations of telomere-associated proteins and inflammasomes initiate many chronic human diseases: a hypothesis.

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. Because heritable autosomal dominant mutations of NLRP3, APP, TREX1, NOTCH3, and Col4A1 are known to provoke inflammatory reactions and damage the brain in a wide variety of diseases, I propose that one or more low abundant, gain-of-function somatic mutations of the same 5 gene families damage the microvasculature of the brain that leads to dementia. This implies that the pathogenic triggers that lead to AD are derived not from external invaders or amyloid but from oxidative damage of our own genes.

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. Recent high-resolution NMR studies of living patients show that lesions in white matter regions of the brain precede the appearance of amyloid deposits and are correlated with damaged small blood vessels. To appreciate the pathogenic potential of damaged small blood vessels in the brain, it is useful to consider the clinical course and the pathogenesis of CADASIL, a heritable arteriopathy that leads to damaged small blood vessels and irreversible dementia. CADASIL is strikingly similar to early onset AD in that it is caused by germ line mutations in NOTCH 3 that generate toxic protein aggregates similar to those attributed to mutant forms of the amyloid precursor protein and presenilin genes. Since NOTCH 3 mutants clearly damage small blood vessels of white matter regions of the brain that lead to dementia, we speculate that both forms of dementia may have a similar pathogenesis, which is to cause ischemic damage by blocking blood flow or by impeding the removal of toxic protein aggregates by retrograde vascular clearance mechanisms.

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 ß 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. Some researchers question whether amyloid is the appropriate target. Others maintain that early, presymptomatic intervention would be a more informative test, and propose large-scale clinical trials in patients who are believed to be in the earliest, and potentially reversible, stages of the disease. This review explores the wisdom of that approach.

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. This essay attempts to describe what we know, and do not know, about the earliest stages of the disease, focusing on the possibility that the initial pathological changes involve oxidative-induced inflammatory damage to small blood vessels. The resulting ischemia activates amyloid-processing enzymes and other proinflammatory factors that eventually compromise neuronal functions, leading, over time, to the complex lesions that characterize advanced disease. The idea that blood vessel damage is primary has a long history and many prior advocates. The novel addition offered here is the speculation that low-abundance, gain-of-function somatic mutations of the amyloid precursor protein may be part of the triggering mechanism.

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. We show that mature AHNAK1-deficient CTLs exhibit reduced Ca(v)1.1 alpha1 subunit expression (also referred to as L-type calcium channels or alpha1S pore-forming subunits), which recently were suggested to play a role in calcium entry into CD4(+) T cells. AHNAK1-deficient CTLs show marked reduction in granzyme-B production, cytolytic activity, and IFN-gamma secretion after T cell receptor stimulation. Our results demonstrate an AHNAK1-dependent mechanism controlling calcium entry during CTL effector function.

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. I describe here how studies of red blood cell membrane proteins evolved and how results from those studies still inform present-day research.

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. AHNAK1-deficient CD4+ T cells responded poorly to TCR stimulation in vitro with low proliferation and low Interleukin-2 production. Furthermore, AHNAK1 deficiency resulted in a reduced calcium influx upon TCR crosslinking and subsequent poor activation of the transcription factor NFAT. AHNAK1 was required for plasma membrane expression of L-type calcium channels alpha 1S (Cav1.1), probably through its interaction with the beta regulatory subunit. Thus, AHNAK1 plays an essential role in T cell Ca2+ signaling through Cav1 channels, triggered via TCR activation; therefore, AHNAK1 is a potential target for therapeutic intervention.

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. Based on the presence of shared amino acid sequences containing GxxG motifs, I speculate that accumulations of intramembranous Abeta peptides might affect the functions of amyloid precursor protein itself and the assembly of the PS1, Aph1, Pen 2, Nicastrin complex.

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. & Bishop, J. M. (1992) Proc. Natl. Acad. Sci. USA 89, 5472-5476], we created AHNAK null mice by homologous recombination. Homozygous knockouts showed no obvious phenotype, but revealed instead a second AHNAK-like molecule, provisionally designated AHNAK2. Like the original AHNAK, AHNAK2 is a 600-kDa protein composed of a large number of highly conserved repeat segments. Structural predictions suggest that the repeat segments of both AHNAKs may have as their basic framework a series of linked, antiparallel beta-strands similar to those found in beta-propeller proteins. Both AHNAKs appear to localize to Z-band regions of mouse cardiomyocytes and cosediment with membrane vesicles containing the dihydropyridine receptor, which is consistent with earlier reports that the AHNAKs are linked to L-type calcium channels and can be phosphorylated by protein kinase A. The localization of the AHNAKs in close proximity to transverse tubule membranes and Z-band regions of cardiac sarcomeres raise the possibility that they might be involved in regulating excitation/contraction coupling of cardiomyocytes, but other studies indicate that the association of AHNAKs with calcium channel proteins is more widespread. AHNAK2 is predicted to have a PDZ domain within its N-terminal, nonrepeating domain, which may mediate these interactions.