David Teplow

• Ph.D.
• University of California, Los Angeles

Synuclein (αS), the causative protein of Parkinson’s disease and other α-synucleinopathies, aggregates from a low molecular weight form (LMW-αS) to a high molecular weight αS oligomer (HMW-αSo). Aggregated αS accumulates intracellularly, induces intrinsic apoptosis, is released extracellularly, and appears to propagate disease through prion-like sp...

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 (Aβ42), a peptide strongly associated with AD. Previous studies in mice, demonstrated that targeted overexpression o...

Background Excessive accumulation of amyloid β‐protein (Aβ) is one of the primary mechanisms that leads to neuronal death with phosphorylated tau in the pathogenesis of Alzheimer’s disease (AD). Protofibrils, one of the high‐molecular‐weight Aβ oligomers (HMW‐Aβo), are implicated to be important targets of disease modifying therapy of AD. We previo...

Amyloid-β (Aβ) aggregation intermediates, including oligomers and protofibrils (PFs), have attracted attention as neurotoxic aggregates in Alzheimer's disease. However, due to the complexity of the aggregation pathway, the structural dynamics of aggregation intermediates and how drugs act on them have not been clarified. Here we used high-speed ato...

Early diagnosis of Alzheimer’s Disease (AD) is critical for disease prevention and cure. However, currently, techniques with the required high sensitivity and specificity are lacking. Recently, with the advances and increased accessibility of data analysis tools, such as machine learning, research efforts have increasingly focused on using these co...

Oligomers of the amyloid β-protein (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD) through their toxicity towards neurons. Understanding the process of oligomerization may contribute to the development of therapeutic agents, but this has been difficult due to the complexity of oligomerization and the metastability of the o...

The amyloid β-protein is an intrinsically disordered protein that has the potential to assemble into myriad structures, including oligomers and fibrils. These structures are neurotoxic and are thought to initiate a cascade of events leading to Alzheimer's disease. Understanding this pathogenetic process and elucidating targets for drug therapy depe...

Excessive accumulation of amyloid β-protein (Aβ) is one of the primary mechanisms that leads to neuronal death with phosphorylated tau in the pathogenesis of Alzheimer's disease (AD). Protofibrils, one of the high-molecular-weight Aβ oligomers (HMW-Aβo), are implicated to be important targets of disease modifying therapy of AD. We previously report...

Background Excessive accumulation of β‐amyloid peptide (Aβ) is one of the major mechanisms that cause neuronal death in Alzheimer's disease (AD). We’ve previously shown protofibrils, one of the accumulated Aβ oligomers, are implicated to play a major role. Vitamin B12 (VB12) is an important micronutrient required for brain development and has recei...

Background Amyloid β protein (Aβ) molecules that may contribute to Alzheimer's disease (AD) form low molecular weight (LMW‐Aβ), high molecular weight oligomer (HMW‐Aβ) such as protofibrils, and ultimately fibrils. Recent evidence suggests that oxidative stress and plasma membrane damage induced by soluble Aβ oligomers elicit neurotoxicity and play...

Fibril formation is an obligatory process in amyloid diseases and is characterized by nucleation and elongation phases that result in the formation of long filaments with cross-β sheet structure. The kinetics of this process, as well as that of secondary nucleation, is controlled by a variety of factors, including nucleus (seed) structure, monomer...

Interleukin-34 (IL-34) is a recently discovered cytokine that acts as a second ligand of the colony stimulating factor 1 receptor (CSF1R) in addition to macrophage colony-stimulating factor (M-CSF). Similar to M-CSF, IL-34 also stimulates bone marrow (BM)-derived monocyte survival and differentiation into macrophages. Growing evidence suggests that...

Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ42) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ42 oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to th...

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-c...

Surface enhanced Raman spectroscopy (SERS) holds great promise in biosensing because of its single‐molecule, label‐free sensitivity. We describe here the use of a graphene–gold hybrid plasmonic platform that enables quantitative SERS measurement. Quantification is enabled by normalizing analyte peak intensities to that of the graphene G peak. We sh...

Amyloid β‐protein (Aβ) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aβ species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated...

Protein and peptide oligomers are thought to play important roles in the pathogenesis of a number of neurodegenerative diseases. For this reason, considerable effort has been devoted to understanding the oligomerization process and to determining structure-activity relationships among the many types of oligomers that have been described. We discuss...

Amyloid β‐protein (Aβ) self‐association is one process linked to the development of Alzheimer's disease (AD). Aβ peptides, including its most abundant forms, Aβ40 and Aβ42, are associated with the two predominant neuropathologic findings in AD, vascular and parenchymal amyloidosis, respectively. Efforts to develop therapies for AD often have focuse...

Amyloid β-protein (Aβ) oligomers are emerging as potent neurotoxic species in Alzheimer’s disease pathogenesis. Detailed characterization of oligomer structure and dynamics are necessary to develop oligomer-specific therapeutic agents. However, oligomers exist transiently, which complicates their structural analysis. One approach to mitigate these...

Amyloid β-protein (Aβ) assembly is a seminal process in Alzheimer's disease. Elucidating the mechanistic features of this process is thought to be vital for the design and targeting of therapeutic agents. Com-putational studies of the most pathologic form of Aβ, the 42-residue Aβ42 peptide, have suggested that hydrogen bonding involving Ser 26 may...

Amyloid β-protein (Aβ) assembly is hypothesized to be a seminal neuropathologic event in Alzheimer’s disease (AD). We used an unbiased D-amino acid substitution strategy to determine structure-assembly relationships of 76 different Aβ40 and Aβ42 peptides. We determined the effects of the substitutions on peptide oligomerization, secondary structure...

Intrinsically disordered protein (IDP) conformers occupy large regions of conformational space and display relatively flat energy surfaces. Amyloid-forming IDPs, unlike natively folded proteins, have folding trajectories that frequently involve movements up shallow energy gradients prior to the “downhill” folding leading to fibril formation. We sug...

Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by bone marrow (BM)-derived myelomonocytes, regulates immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes and macrophages by immunomodulation using glatiramer acetate (GA) or by peripheral blood enrichment with BM...

The neuropathology of Alzheimer's disease ( AD ) includes amyloid plaque formation by the amyloid β‐protein (Aβ) and intracellular paired helical filament formation by tau protein. These neuropathogenetic features correlate with disease progression and have been revealed in brains of AD patients using positron emission tomography (PET). One of the...

Evidence suggests that amyloid β-protein (Aβ) oligomers may be seminal pathogenic agents in Alzheimer's disease (AD). If so, developing oligomer-targeted therapeutics requires an understanding of oligomer structure. This has been difficult due to the instability of these non-covalently associated Aβ assemblies. We previously used rapid, zero-length...

A key pathogenic agent in Alzheimer's disease (AD) is the amyloid β-protein (Aβ), which self- assembles into a variety of neurotoxic structures. Establishing structure-activity relationships for these assemblies, which is critical for proper therapeutic target identification and design, requires aggregation and neurotoxicity experiments that are pr...

Significance Amyloid fibril formation underlies the pathogenesis of a large number of diseases. Among the neurodegenerative diseases, the process is prominent in Alzheimer’s disease. Fibril elongation has been thought to be a nucleation-dependent process that faithfully duplicates nucleus structure as each monomer adds to the fibril end. Polymorphi...

We investigate the relationship between 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 transm...

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 a...

Amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Aβ and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases...

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 dy...

A variety of species express the amyloid β-protein (Aβ). Those species expressing Aβ with primary structure identical to that expressed in humans have been found to develop amyloid deposits and Alzheimer's disease-like neuropathology. In contrast, the Aβ sequence in mice and rats contains three amino acid substitutions, Arg5Gly, His13Arg, and Tyr10...

Oligomeric states of the amyloid β-protein (Aβ) appear to be causally related to Alzheimer's disease (AD). Recently, two familial mutations in the amyloid precursor protein gene have been described, both resulting in amino acid substitutions at Ala2 (A2) within Aβ. An A2V mutation causes autosomal recessive early onset AD. Interestingly, heterozygo...

A popular working hypothesis of Alzheimer's disease causation is amyloid β-protein oligomers are the key neuropathogenetic agents. To rigorously elucidate the role of oligomers requires the production of stable oligomers of each size. We previously used zero-length photochemical cross-linking to enable stabilization, isolation, and determination of...

Epidemiological evidence that red wine consumption negatively correlates with risk of AD has led to experimental studies demonstrating that grape seed extracts inhibit the aggregation and oligomerization of Aβ in vitro and ameliorate neuropathology and behavioral deficits in a mouse model of AD. The active agent in the extracts is a mixed populatio...

Significance Alzheimer’s disease (AD) involves neuron dysfunction and loss. This brain damage is thought to be caused by a small protein, the amyloid β-protein (Aβ), which forms aggregates that are neurotoxic. This neurotoxicity has been explained by multiple mechanisms. We reveal here a new neurotoxic mechanism that involves the interaction betwee...

Five different mutants of [Leu-5] Enkephalin YGGFL peptide have been investigated for fibril formation propensities. The early oligomer structures have been probed with a combination of ion-mobility mass spectrometry and computational modeling. The two peptides YVIFL and YVVFL form oligomers and amyloid-like fibrils. YVVFV shows an early stage olig...

One of the earliest events in amyloid β-protein (Aβ) self-association is nucleation of Aβ monomer folding through formation of a turn at Gly25-Lys28. We report here the effects of structural changes at the center of the turn, Gly25-Ser26, on Aβ42 conformational dynamics and assembly. We used "click peptide" chemistry to quasi-synchronously create A...

The aggregation of a-synuclein (a-Syn) is linked to Parkinson's disease. The mechanism of early aggregation steps and the effect of pathogenic single-point mutations remain elusive. We report here a single-molecule fluorescence study of a-Syn dimerization and the effect of mutations. Specific interactions between tethered fluorophore-free a-Syn mon...

The oligomer cascade hypothesis, which states that oligomers are the initiating pathologic agents in Alzheimer's disease, has all but supplanted the amyloid cascade hypothesis, which suggested that fibers were the key etiologic agents in Alzheimer's disease. We review here the results of in vivo, in vitro and in silico studies of amyloid β-protein...

Aβ42 and Aβ40 are the two primary alloforms of human amyloid β-protein (Aβ). The two additional C-terminal residues of Aβ42 result in elevated neurotoxicity compared with Aβ40, but the molecular mechanism underlying this effect remains unclear. Here, we used single-molecule force microscopy to characterize interpeptide interactions for Aβ42 and Aβ4...

According to Thomas Kuhn, the success of 'normal science,' the science we all practice on a daily basis, depends on the adherence to, and practice of, a paradigm accepted by the scientific community. When great scientific upheavals occur, they involve the rejection of the current paradigm in favor of a new paradigm that better integrates the facts...

Residue mutations have substantial effects on aggregation kinetics and propensities of amyloid peptides and their aggregate morphologies. Such effects are attributed to conformational transitions accessed by various types of oligomers such as steric zipper or single β-sheet. We have studied the aggregation propensities of six NNQQNY mutants: NVVVVY...

Alzheimer's disease is a devastating disorder that is estimated to affect more than 25 million people worldwide and for which there are no preventive, disease-modifying, or curative therapies. Substantial evidence indicates that the amyloid β-protein (Aβ) is a seminal factor in disease causation and may be a tractable therapeutic target. The abilit...

As immune defects in amyloid-β (Aβ) phagocytosis and degradation underlie Aβ deposition and inflammation in Alzheimer's disease (AD) brain, better understanding of the relation between Aβ phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD p...

Although most cases of Alzheimer's disease (AD) are sporadic, ∼5% of cases are genetic in origin. These cases, known as familial Alzheimer's disease (FAD), are caused by mutations that alter the rate of production or the primary structure of the amyloid β-protein (Aβ). Changes in the primary structure of Aβ alter the peptide's assembly and toxic ac...

Misfolding and aggregation of the amyloid β-protein (Aβ) are hallmarks of Alzheimer's disease. Both processes are dependent on the environmental conditions, including the presence of divalent cations, such as Cu(2+). Cu(2+) cations regulate early stages of Aβ aggregation, but the molecular mechanism of Cu(2+) regulation is unknown. In this study we...

The predominant working hypothesis of Alzheimer's disease is that the proximate pathologic agents are oligomers of the amyloid β-protein (Aβ). "Oligomer" is an ill-defined term. Many different types of oligomers have been reported, and they often exist in rapid equilibrium with monomers and higher-order assemblies. This has made formal structure-ac...

It is now established that the neuropathology of Alzheimer disease (AD) accumulates many years before the expression of overt symptoms. The development of β-amyloid (Aβ) binding ligands that allow identification of Αβ pathology in vivo using PET has enabled identification of persons harboring these changes. Though there are still unanswered questio...

The amyloid β-protein (Aβ), which is present predominately as a 40- or 42-residue peptide, is postulated to play a seminal role in the pathogenesis of Alzheimer's disease (AD). Folding of the Aβ(21-30) decapeptide region is a critical step in the aggregation of Aβ. We report results of constant temperature all-atom molecular dynamics simulations in...

Alzheimer's disease (AD) is linked to the aberrant assembly of the amyloid β-protein (Aβ). The (21)AEDVGSNKGA(30) segment, Aβ(21-30), forms a turn that acts as a monomer folding nucleus. Amino acid substitutions within this nucleus cause familial forms of AD. To determine the biophysical characteristics of the folding nucleus, we studied the biolog...

While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as by limited knowledge regarding their bioavailability, metabolism, and bioactivity, especially in the brain. We recently demonstrated that dietary s...

Cerebral deposition of amyloid β protein (Aβ) is an invariant feature of Alzheimer disease (AD), and epidemiological evidence suggests that moderate consumption of foods enriched with phenolic compounds reduce the incidence of AD. We reported previously that the phenolic compounds myricetin (Myr) and rosmarinic acid (RA) inhibited Aβ aggregation in...

Oligomeric assemblies of the amyloid β-protein, Aβ, are thought to be the proximate neurotoxic agents in Alzheimer's disease (AD). Oligomer formation is a complex process that produces a polydisperse population of metastable structures. For this reason, formal structure-activity correlations, both in vitro and in vivo, have been difficult to accomp...

Quasielastic light scattering (QLS) spectroscopy is a noninvasive optical method for studying the dynamic properties of macromolecular solutions. Its most important application is the determination of diffusion coefficients, from which the sizes of particles in solution may be estimated. The technique thus is particularly useful for monitoring asse...

Oligomeric β-amyloid (Aβ) has recently been linked to synaptic plasticity deficits, which play a major role in progressive cognitive decline in Alzheimer's disease (AD). Here we present evidence that chronic oral administration of carvedilol, a nonselective β-adrenergic receptor blocker, significantly attenuates brain oligomeric β-amyloid content a...

α-Synuclein (αS) assembly has been implicated as a critical step in the development of Lewy body diseases such as Parkinson's disease and dementia with Lewy bodies. Melatonin (Mel), a secretory product of the pineal gland, is known to have beneficial effects such as an antioxidant function and neuroprotection. To elucidate whether Mel has an antias...

Alzheimer’s disease (AD) is a neurodegenerative disorder causing irreversible damage to the brain that culminates in memory loss, cognitive dysfunction, and eventual death. Amyloid beta-protein (Abeta) forms deposits of fibrillar assemblies, which were long believed to be the key etiologic factors of AD. However, recent studies suggest that pre-fib...

A familial form of Alzheimer disease recently was described in a kindred in Osaka, Japan. This kindred possesses an amyloid β-protein (Aβ) precursor mutation within the Aβ coding region that results in the deletion of Glu22 (ΔE22). We report here results of studies of [ΔE22]Aβ40 and [ΔE22]Aβ42 that sought to elucidate the conformational dynamics, o...

Nonfibrillar assemblies of amyloid β-protein (Aβ) are considered to play primary roles in Alzheimer disease (AD). Elucidating the assembly pathways of these specific aggregates is essential for understanding disease pathogenesis and developing knowledge-based therapies. However, these assemblies cannot be monitored in vivo, and there has been no re...

Nonfibrillar assemblies of amyloid β-protein (Aβ) are considered to play primary roles in Alzheimer disease (AD). Elucidating the assembly pathways of these specific aggregates is essential for understanding disease pathogenesis and developing knowledge-based therapies. However, these assemblies cannot be monitored in vivo, and there has been no re...

Amyloid β-protein self-assembly appears to play an important role in the pathogenesis of Alzheimer’s disease (AD). Recently, a new familial form of AD was described in a Japanese kindred. This kindred expressed an APP mutation within the Aβ coding region that resulted in the deletion of codon 693. This codon encodes Glu22 within Aβ. We report here...

Aggregation of microtubule-associated protein tau into insoluble intracellular neurofibrillary tangles is a characteristic hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, including progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, frontotemporal dementias with Parkinsonism linked to ch...

Mutations in the amyloid beta-protein (Abeta) precursor gene cause autosomal dominant Alzheimer disease in a number of kindreds. In two such kindreds, the English and the Tottori, the mutations produce amyloid beta-proteins containing amino acid substitutions, H6R and D7N, respectively, at the peptide N terminus. To elucidate the structural and bio...

Oligomers of the amyloid β-protein (Aβ) play an important role in Alzheimer's disease (AD). We hypothesized that AD patients have a central nervous system environment that promotes Aβ oligomerization. We investigated the effect of cerebrospinal fluid (CSF) from 33 patients with AD and 33 age-matched, non-demented controls on oligomerization of Aβ1-...

Oligomers of amyloid beta-protein (Abeta) play a central role in the pathology of Alzheimer's disease. Of the two predominant Abeta alloforms, Abeta(1-40) and Abeta(1-42), Abeta(1-42) is more strongly implicated in the disease. We elucidated the structural characteristics of oligomers of Abeta(1-40) and Abeta(1-42) and their Arctic mutants, [E22G]A...

The oligomerization of amyloid β-protein (Aβ) is a seminal event in the neurodegenerative process in Alzheimer's disease (AD). Aβ40 and Aβ42, the two predominant forms of Aβ, display different aggregation behavior which underlies the special pathogenetic significance of Aβ42. Previous computational studies have revealed that a turn-like structure e...

Amyloid beta-protein (Abeta) self-assembly is linked strongly to Alzheimer's disease. We found that PP-Leu, a tridecapeptide analogue of broad-spectrum antiviral peptides termed theta-defensins, potently inhibits Abeta oligomer and fibril formation. This effect appeared to be mediated through sequestration of the amyloidogenic Abeta peptide in coll...

Amyloid beta-protein (Abeta) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). "Oligomer" is an ill-defined term because many kinds have been reported and they often exist in rapid equilibrium with monomers and higher-order assemblies. We report here results of studies in which specific oligomers have been stabilized structura...

Amyloid beta-protein (Abeta) assemblies are thought to play primary roles in Alzheimer disease (AD). They are considered to acquire surface tertiary structures, not present in physiologic monomers, that are responsible for exerting toxicity, probably through abnormal interactions with their target(s). Therefore, Abeta assemblies having distinct sur...

Alzheimer's disease (AD) is an archetype of a class of diseases characterized by abnormal protein deposition. in each case, deposition manifests itself in the form of amyloid deposits composed of fibrils of otherwise normal, soluble proteins or peptides. An ever-increasing body of genetic, physiologic, and biochemical data supports the hypothesis t...

Understanding the structural and assembly dynamics of the amyloid beta-protein (Abeta) has direct relevance to the development of therapeutic agents for Alzheimer disease. To elucidate these dynamics, we combined scanning amino acid substitution with a method for quantitative determination of the Abeta oligomer frequency distribution, photo-induced...