Distinct Pools of β-Amyloid in Alzheimer Disease–Affected Brain

Steinerman, Joshua R.; Irizarry, Michael C.; Scarmeas, Nikolaos; Raju, Susan; Brandt, Jason; Albert, Marilyn; Blacker, Deborah; Hyman, Bradley T.; Stern, Yaakov

doi:10.1001/archneur.65.7.906

Cited by 99 publications

(71 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We measured Aβ 42 pool containing intracellular and membrane-associated Aβ 42 that may be more closely related to the expression of AD signs than other measured Aβ 42 species (Steinerman et al, 2008). Tissue was homogenized in a buffer containing SDS 2%, Tris-HCl (10 mM, pH 7.4), protease inhibitors (Complete Protease Inhibitor Cocktail, Roche), and phosphatase inhibitors (0.1 mM Na 3 VO 4 , 1 mM NaF).…”

Section: Determination Of Aβ Levelsmentioning

confidence: 99%

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

Cuadrado‐Tejedor

García‐Barroso

Sánchez‐Arias

et al. 2016

Neuropsychopharmacol

View full text Add to dashboard Cite

The targeting of two independent but synergistic enzymatic activities, histone deacetylases (HDACs, class I and HDAC6) and phosphodiesterase 5 (PDE5), has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMPresponsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission. Thus, CM-414 may serve as the starting point to discover balanced dual inhibitors with an optimal efficacy and safety profile for clinical testing on AD patients.

show abstract

Section: Determination Of Aβ Levelsmentioning

confidence: 99%

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

Cuadrado‐Tejedor

García‐Barroso

Sánchez‐Arias

et al. 2016

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…In the Tg2576 model, memory impairment begins when A␤ dimers start to accumulate (i.e., ϳ6 months before plaque formation) (Kawarabayashi et al, 2004). In AD patients, soluble intracellular and membrane-associated A␤ in temporal neocortex is more closely related to AD symptoms than other A␤ species (Steinerman et al, 2008). A␤ binding to cell membranes is therefore not negligible and could disrupt their fluidity and, therefore, synaptic activity and neurotransmission.…”

Section: App Swe /Ps1/ccr2mentioning

confidence: 99%

CC Chemokine Receptor 2 Deficiency Aggravates Cognitive Impairments and Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Naert¹,

Rivest²

2011

J. Neurosci.

164

125

View full text Add to dashboard Cite

Circulating monocytoid cells have the ability to infiltrate nervous tissue, differentiate into microglia, and clear amyloid-␤ (A␤) from the brain of mouse models of Alzheimer's disease. Interaction between the chemokine CCL2 and its CC chemokine receptor 2 (CCR2) plays a critical role in the recruitment of inflammatory monocytes into the injured/diseased brain. Here, we show that CCR2 deficiency aggravates mnesic deficits and amyloid pathology in transgenic mice expressing the chimeric mouse/human ␤-amyloid precursor protein and presenilin 1 (APP Swe /PS1). Indeed, memory impairment was accelerated and enhanced in APP Swe /PS1/CCR2 Ϫ/Ϫ mice. Apparition of cognitive decline occurred earlier (i.e., at 3 months of age before plaque formation) and correlated with intracellular accumulation of soluble oligomeric forms of A␤. Memory deficits worsened with age and were aggravated in APP Swe /PS1/CCR2 Ϫ/Ϫ mice compared with their respective control groups. Soluble A␤ assemblies increased significantly in APP Swe /PS1 mice in a context of CCR2 deficiency, whereas the plaque load remained relatively similar in the brain of aging APP Swe /PS1 and APP Swe /PS1/CCR2 Ϫ/Ϫ mice. However, CCR2 deficiency stimulated the expression of TGF-␤1, TGF-␤ receptors, and CX 3 CR1 transcripts in plaque-associated microglia, a pattern that is characteristic of an antiinflammatory subset of myeloid cells. A decreased expression of CCR2 could play a potential role in the etiology of Alzheimer's disease, a neurodegenerative pathology that could be treated by a genetic upregulation of the transgene in monocytoid cells.

show abstract

“…However, intracellular A␤ 42 and A␤ 40 have been demonstrated in brains of AD patients (Gouras et al, 2000). Moreover, Steinerman et al (2008) reported that intracellular and membrane-associated A␤, especially A␤ 42 in the temporal neocortex, may be more closely related to AD symptoms than other A␤ species that they examined. Although these authors did not attempt to describe the effects of monomers and oligomers differentially, the presence of intracellular A␤ 42 has been clearly demonstrated in diseased human brains.…”

Section: Distinct Effects Of Extracellular and Intracellular A␤mentioning

confidence: 99%

Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a

Yamamoto¹,

Ueta²,

Wang³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

It is proposed that intracellular amyloid-␤ (A␤), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular A␤ affects neuronal properties. This was done by injecting A␤ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular A␤ is accumulated innately. In rats, intracellular application of a mixed A␤ 1-42 preparation containing both oligomers and monomers, but not a monomeric preparation of A␤ 1-40 , broadened spike width and augmented Ca 2ϩ influx via voltage-dependent Ca 2ϩ channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca 2ϩ -activated K ϩ (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca 2ϩ influx was caused by elongated spike duration, but not attributable to direct Ca 2ϩ channel modulation by A␤ 1-42 . The A␤ 1-42 -induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by A␤ 1-42 , which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the A␤ 1-42 effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular A␤ 1-42 is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.

show abstract

Distinct Pools of β-Amyloid in Alzheimer Disease–Affected Brain

Cited by 99 publications

References 37 publications

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

CC Chemokine Receptor 2 Deficiency Aggravates Cognitive Impairments and Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a

Contact Info

Product

Resources

About