Bridging Integrator 1 (BIN1, rs6733839) and Sex Are Moderators of Vascular Health Predictions of Memory Aging Trajectories.

BACKGROUND: A promising risk loci for sporadic Alzheimer's disease (AD), Bridging Integrator 1 (BIN1), is thought to operate through the tau pathology pathway. OBJECTIVE: We examine BIN1 risk for a moderating role with vascular health (pulse pressure; PP) and sex in predictions of episodic memory trajectories in asymptomatic aging adults. METHODS: The sample included 623 participants (Baseline Mean age = 70.1; 66.8% female) covering a 44-year longitudinal band (53-97 years). With an established memory latent variable arrayed as individualized trajectories, we applied Mplus 8.5 to determine the best fitting longitudinal growth model. Main analyses were conducted in three sequential phases to investigate: 1) memory trajectory prediction by PP, 2) moderation by BIN1 genetic risk, and 3) stratification by sex. RESULTS: We first confirmed that good vascular health (lower PP) was associated with higher memory level and shallower decline and males were more severely affected by worsening PP in both memory performance and longitudinal decline. Second, the PP prediction of memory trajectories was significant for BIN1 C/C and C/T carriers but not for persons with the highest AD risk (T/T homozygotes). Third, when further stratified by sex, the BIN1 moderation of memory prediction by PP was selective for females. CONCLUSION: We observed a novel interaction whereby BIN1 (linked with tauopathy in AD) and sex sequentially moderated a benchmark PP prediction of differential memory decline in asymptomatic aging. This multi-modal biomarker interaction approach, disaggregated by sex, can be an effective method for enhancing precision of AD genetic risk assessment.

Genetic Depletion of Amylin/Calcitonin Receptors Improves Memory and Learning in Transgenic Alzheimer's Disease Mouse Models.

Based upon its interactions with amyloid ß peptide (Aß), the amylin receptor, a class B G protein-coupled receptor (GPCR), is a potential modulator of Alzheimer's disease (AD) pathogenesis. However, past pharmacological approaches have failed to resolve whether activation or blockade of this receptor would have greater therapeutic benefit. To address this issue, we generated compound mice expressing a human amyloid precursor protein gene with familial AD mutations in combination with deficiency of amylin receptors produced by hemizygosity for the critical calcitonin receptor subunit of this heterodimeric GPCR. These compound transgenic AD mice demonstrated attenuated responses to human amylin- and Aß-induced depression of hippocampal long-term potentiation (LTP) in keeping with the genetic depletion of amylin receptors. Both the LTP responses and spatial memory (as measured with Morris water maze) in these mice were improved compared to AD mouse controls and, importantly, a reduction in both the amyloid plaque burden and markers of neuroinflammation was observed. Our data support the notion of further development of antagonists of the amylin receptor as AD-modifying therapies.

Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing.

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.

Amylin Receptor: A Potential Therapeutic Target for Alzheimer's Disease.

Alzheimer'sdisease (AD) is a progressive neurodegenerative disorder, characterized by senile plaques constituting extracellular deposits of ß-amyloid (Aß) fibrils. Since Aß accumulation in the brain is considered an early event preceding, by decades, cognitive dysfunction, disease-modifying treatments are aimed at facilitating clearance of this protein from the brain or ameliorating its toxic effects. Recent studies have identified the amylin receptor as a capable mediator of the deleterious actions of Aß and furthermore, administration of amylin receptor-based peptides has been shown to improve spatial memory and learning in transgenic mouse models of AD. Here, by discussing available evidence, we posit that the amylin receptor could be considered a potential therapeutic target for AD, and present the rationale for using amylin receptor antagonists to treat this debilitating condition.

Pramlintide Antagonizes Beta Amyloid (Aß)- and Human Amylin-Induced Depression of Hippocampal Long-Term Potentiation.

Accumulation of amyloid-ß peptide (Aß) is a pathological hallmark of Alzheimer's disease (AD). We have previously demonstrated that electrophysiological and neurotoxic effects of Aß and human amylin are expressed via the amylin receptor. Recently, pramlintide, a synthetic analog of amylin, has been reported to improve cognitive function in transgenic AD mouse models. In this study, we examined the effects of pramlintide on Aß1-42 and human amylin-evoked depression of long-term potentiation (LTP) at Schaeffer collateral-CA1 hippocampal synapses. In mouse hippocampal brain slices, field excitatory postsynaptic potentials (fEPSPs) were recorded from the stratum radiatum layer of the CA1 area in response to electrical stimulation of Schaeffer collateral afferents and LTP induced by 3-theta-burst stimulation (TBS) protocol. Aß1-42 (50 nM) and human amylin (50 nM), but not Aß42-1 (50 nM), depressed LTP. Pre-application of pramlintide (250 nM) blocked Aß- and human amylin-induced reduction of LTP without affecting baseline transmission or LTP. We also examined the effects of pramlintide on LTP in transgenic mice (TgCRND8) that over-express amyloid precursor protein. In contrast to wild-type controls, where robust LTP was observed, 10- to 12-month-old TgCRND8 mice show blunted LTP. In TgCRND8 mice, basal LTP is enhanced by application of pramlintide. Our data indicate that pramlintide acts as a functional amylin receptor antagonist to reverse the effects of Aß1-42 and human amylin on LTP and also increases LTP in transgenic mice that demonstrate increased ambient brain amyloid levels. Amylin receptor antagonists may thus serve as potentially useful therapeutic agents in treatment of AD.

Histamine induces the production of matrix metalloproteinase-9 in human astrocytic cultures via H1-receptor subtype.

Accumulation of ß-amyloid (Aß) protein within the brain is a neuropathological hallmark of Alzheimer's disease (AD). One strategy to facilitate Aß clearance from the brain is to promote Aß catabolism. Matrix metalloproteinase-9 (MMP-9), a member of the family of Zn(+2)-containing endoproteases, known to be expressed and secreted by astrocytes, is capable of degrading Aß. Histamine, a major aminergic brain neurotransmitter, stimulates the production of MMP-9 in keratinocytes through the histamine H1 receptor (H1R). In the present study, we show that histamine evokes a concentration- and calcium-dependent release of MMP-9 from human astrocytic U373 cells and primary cultures of human and rat astrocytes through the H1R subtype. Activation of H1R on astrocytes elevated intracellular levels of Ca(2+) that was accompanied by time-dependent increases in MAP kinase p44/p42 and PKC. In-cell western blots revealed dose-dependent increases in both enzymes, confirming involvement of these signal transduction pathways. We next investigated the extent of recombinant human MMP-9 (rhMMP-9) proteolytic activity on soluble oligomeric Aß (soAß). Mass spectrometry demonstrated time-dependent cleavage of soAß (20 µM), but not another amyloidogenic protein amylin, upon incubation with rhMMP-9 (100 nM) at 1, 4 and 17 h. Furthermore, Western blots showed a shift in soAß equilibrium toward lower order, less toxic monomeric species. In conclusion, both MAPK p44/p42 and PKC pathways appear to be involved in histamine-upregulated MMP-9 release via H1Rs in astrocytes. Furthermore, MMP-9 appears to cleave soAß into less toxic monomeric species. Given the key role of histamine in MMP-9 release, this neurotransmitter may serve as a potential therapeutic target for AD.

Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity.

Alzheimer disease (AD) is characterized neuropathologically by synaptic disruption, neuronal loss, and deposition of amyloid ß (Aß) protein in brain structures that are critical for memory and cognition. There is increasing appreciation, however, that astrocytes, which are the major non-neuronal glial cells, may play an important role in AD pathogenesis. Unlike neurons, astrocytes are resistant to Aß cytotoxicity, which may, in part, be related to their greater reliance on glycolytic metabolism. Here we show that, in cultures of human fetal astrocytes, pharmacological inhibition or molecular down-regulation of a main enzymatic regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3), results in increased accumulation of Aß within and around astrocytes and greater vulnerability of these cells to Aß toxicity. We further investigated age-dependent changes in PFKFB3 and astrocytes in AD transgenic mice (TgCRND8) that overexpress human Aß. Using a combination of Western blotting and immunohistochemistry, we identified an increase in glial fibrillary acidic protein expression in astrocytes that paralleled the escalation of the Aß plaque burden in TgCRND8 mice in an age-dependent manner. Furthermore, PFKFB3 expression also demonstrated an increase in these mice, although at a later age (9 months) than GFAP and Aß. Immunohistochemical staining showed significant reactive astrogliosis surrounding Aß plaques with increased PFKFB3 activity in 12-month-old TgCRND8 mice, an age when AD pathology and behavioral deficits are fully manifested. These studies shed light on the unique bioenergetic mechanisms within astrocytes that may contribute to the development of AD pathology.

Role of astrocytic glycolytic metabolism in Alzheimer's disease pathogenesis.

Alzheimer's disease (AD) has historically been considered to arise due to the specific dysfunction and pathology of neurons in brain areas related to cognition. Recent progress indicates that astrocytes play an important role in neurodegenerative processes underlying AD. In this review, we focus on the different glucose metabolism profiles between astrocytes and neurons. In AD, a variety of CNS insults, such as the presence of amyloid protein, trigger reactive astrogliosis, which disrupts normal glycolytic activity in these cells. The compromise of the astrocytic metabolism in turn weakens the integrity of astrocytic-neuronal partnership, damages the normal brain homeostasis, impairs clearance of amyloid, promotes cytokine release and other inflammatory mediators, and over time, leads to neurodegeneration.

The hypothalamic neuropeptide FF network is impaired in hypertensive patients.

BACKGROUND: The human hypothalamus contains the neuropeptide FF (NPFF) neurochemical network. Animal experiments demonstrated that NPFF is implicated in the central cardiovascular regulation. We therefore studied expression of this peptide in the hypothalamus of individuals who suffered from essential hypertension (n = 8) and died suddenly due to acute myocardial infarction (AMI), and compared to that of healthy individuals (controls) (n = 6) who died abruptly due to mechanical trauma of the chest. METHODS: The frozen right part of the hypothalamus was cut coronally into serial sections of 20 µm thickness, and each tenth section was stained immunohistochemically using antibody against NPFF. The central section through each hypothalamic nucleus was characterized by the highest intensity of NPFF immunostaining and thus was chosen for quantitative densitometry. RESULTS: In hypertensive patients, the area occupied by NPFF immunostained neuronal elements in the central sections through the suprachiasmatic nucleus (SCh), paraventricular hypothalamic nucleus (Pa), bed nucleus of the stria terminalis (BST), perinuclear zone (PNZ) of the supraoptic nucleus (SON), dorso- (DMH), ventromedial (VMH) nuclei, and perifornical nucleus (PeF) was dramatically decreased compared to controls, ranging about six times less in the VMH to 15 times less in the central part of the BST (BSTC). The NPFF innervation of both nonstained neuronal profiles and microvasculature was extremely poor in hypertensive patients compared to control. CONCLUSIONS: The decreased NPFF expression in the hypothalamus of hypertensive patients might be a cause of impairment of its interaction with other neurochemical systems, and thereby might be involved in the pathogenesis of the disease.

The prion protein modulates A-type K+ currents mediated by Kv4.2 complexes through dipeptidyl aminopeptidase-like protein 6.

Widely expressed in the adult central nervous system, the cellular prion protein (PrP(C)) is implicated in a variety of processes, including neuronal excitability. Dipeptidyl aminopeptidase-like protein 6 (DPP6) was first identified as a PrP(C) interactor using in vivo formaldehyde cross-linking of wild type (WT) mouse brain. This finding was confirmed in three cell lines and, because DPP6 directs the functional assembly of K(+) channels, we assessed the impact of WT and mutant PrP(C) upon Kv4.2-based cell surface macromolecular complexes. Whereas a Gerstmann-Sträussler-Scheinker disease version of PrP with eight extra octarepeats was a loss of function both for complex formation and for modulation of Kv4.2 channels, WT PrP(C), in a DPP6-dependent manner, modulated Kv4.2 channel properties, causing an increase in peak amplitude, a rightward shift of the voltage-dependent steady-state inactivation curve, a slower inactivation, and a faster recovery from steady-state inactivation. Thus, the net impact of wt PrP(C) was one of enhancement, which plays a critical role in the down-regulation of neuronal membrane excitability and is associated with a decreased susceptibility to seizures. Insofar as previous work has established a requirement for WT PrP(C) in the Aß-dependent modulation of excitability in cholinergic basal forebrain neurons, our findings implicate PrP(C) regulation of Kv4.2 channels as a mechanism contributing to the effects of oligomeric Aß upon neuronal excitability and viability.

Amylin receptor: a common pathophysiological target in Alzheimer's disease and diabetes mellitus.

Amylin (islet amyloid polypeptide) and amyloid-beta (Aß) protein, which are deposited within pancreatic islets of diabetics and brains of Alzheimer's patients respectively, share many biophysical and physiological properties. Emerging evidence indicates that the amylin receptor is a putative target receptor for the actions of human amylin and Aß in the brain. The amylin receptor consists of the calcitonin receptor dimerized with a receptor activity-modifying protein and is widely distributed within central nervous system. Both amylin and Aß directly activate this G protein-coupled receptor and trigger multiple common intracellular signal transduction pathways that can culminate in apoptotic cell death. Moreover, amylin receptor antagonists can block both the biological and neurotoxic effects of human amylin and Aß. Amylin receptors thus appear to be involved in the pathophysiology of Alzheimer's disease and diabetes, and could serve as a molecular link between the two conditions that are associated epidemiologically.

Role of amylin and its receptors in neurodegeneration.

Amylin (islet amyloid polypeptide) and amyloid beta protein (Aß), identified as proteinaceous deposits within the pancreas of diabetics and the brain of Alzheimer's patients respectively, share many biophysical, physiological and neurotoxic properties. Although no specific ß receptor" has been identified, emerging evidence suggests that the amylin receptor serves a putative target receptor for the actions of Aß in the brain. The amylin receptor consists of a calcitonin receptor dimerized with receptor activity-modifying proteins and is widely distributed within central nervous system. Aß can directly activate this G protein-coupled receptor and trigger multiple intracellular signal transduction messengers and pathways that include calcium, cAMP, ERK1/2 and Fos. Growing evidence suggests that amylin and amylin receptors are involved in many aspects of neurodegenerative pathophysiology. Developing therapeutic strategies aimed at modulating amylin receptor function may prove useful for treatment of neurodegenerative diseases such as Alzheimer's disease.

Role of neuropeptide FF in central cardiovascular and neuroendocrine regulation.

Neuropeptide FF (NPFF) is an octapeptide belonging to the RFamide family of peptides that have been implicated in a wide variety of physiological functions in the brain including central cardiovascular and neuroendocrine regulation. The effects of these peptides are mediated via NPFF1 and NPFF2 receptors that are abundantly expressed in the rat and human brain. Herein, we review evidence for the role of NPFF in central regulation of blood pressure particularly within the brainstem and the hypothalamic paraventricular nucleus (PVN). At a cellular level, NPFF demonstrates distinct responses in magnocellular and parvocellular neurons of the PVN, which regulate the secretion of neurohypophyseal hormones and sympathetic outflow, respectively. Finally, the presence of NPFF system in the human brain and its alterations within the hypertensive brain are discussed.

Distinct morphological and electrophysiological properties of an elk prion peptide.

A key event in prion diseases is the conversion of the prion protein (PrP) from its native α-helical conformation to a misfolded, ß-sheet rich conformation. Thus, preventing or reversing PrP misfolding could provide a means to disrupt prion disease progression and transmission. However, determining the structure of misfolded PrP has been notoriously difficult due to its inherent heterogeneity and aggregation behavior. For these reasons, simplified peptide fragments have been used as models that recapitulate characteristics of full-length PrP, such as amyloid-like aggregation and fibril formation, and in vitro toxicity. We provide a biochemical and structural comparison of PrP(127-147) peptides from elk, bovine and hamster using electrophysiology, electron microscopy and fluorescence. Our results demonstrate that the PrP(127-147) peptides adopt distinct populations of fibril structures. In addition, the elk PrP(127-147) peptide is unique in its ability to enhance Thioflavin T fluorescence and its ability to modulate neuronal ion channel conductances.

Beta amyloid-induced depression of hippocampal long-term potentiation is mediated through the amylin receptor.

Alzheimer's disease (AD) is characterized by accumulation of amyloid-ß peptide (Aß) in the brain regions that subserve memory and cognition. The amylin receptor is a potential target receptor for expression of the deleterious actions of soluble oligomeric Aß species. We investigated whether the amylin receptor antagonist, AC253, neutralizes the depressant effects of Aß(1-42) and human amylin on hippocampal long-term potentiation (LTP). Furthermore, we examined whether depressed levels of LTP observed in transgenic mice, which overexpress amyloid precursor protein (TgCRND8), could be restored with AC253. In mouse hippocampal brain slices, field EPSPs were recorded from the stratum radiatum layer of the CA1 area (cornu ammonis 1 region of the hippocampus) in response to electrical stimulation of Schaeffer collateral afferents. LTP was induced by 3-theta burst stimulation protocols. Aß(1-42) (50 nM) and human amylin (50 nM), but not Aß(42-1) (50 nM), depressed LTP evoked using both stimulation protocols. Preapplication of AC253 (250 nM) blocked Aß- and human amylin-induced reduction of LTP without affecting baseline transmission or LTP on its own. In contrast to wild-type controls, where robust LTP is observed, 6- to 12-month-old TgCRND8 mice show blunted LTP that is significantly enhanced by application of AC253. Our data demonstrate that the effects of Aß(1-42) and human amylin on LTP are expressed via the amylin receptor, and moreover, blockade of this receptor increases LTP in transgenic mice that show increased brain amyloid burden. Amylin receptor antagonists could serve as potentially useful therapeutic agents in AD.

The P's and Q's of cellular PrP-Aß interactions.

Prion disease research has opened up the "black-box" of neurodegeneration, defining a key role for protein misfolding wherein a predominantly alpha-helical precursor protein, PrP (C), is converted to a disease-associated, ß-sheet enriched isoform called PrP (Sc). In Alzheimer disease (AD) the Aß peptide derived from the ß-amyloid precuror protein APP folds in ß-sheet amyloid. Early thoughts along the lines of overlap may have been on target, (1) but were eclipsed by a simultaneous (but now anachronistic) controversy over the role of PrP (Sc) in prion diseases. (2) (,) (3) Nonetheless, as prion diseases such as Creutzfeldt-Jakob Disease (CJD) are themselves rare and can include an overt infectious mode of transmission, and as familial prion diseases and familial AD involve different genes, an observer might reasonably have concluded that prion research could occasionally catalyze ideas in AD, but could never provide concrete overlaps at the mechanistic level. Surprisingly, albeit a decade or three down the road, several prion/AD commonalities can be found within the contemporary literature. One important prion/AD overlap concerns seeded spread of Aß aggregates by intracerebral inoculation much like prions, (4) and, with a neuron-to-neuron 'spreading' also reported for pathologic forms of other misfolded proteins, Tau (5) (,) (6) and α-synuclein in the case of Parkinson Disease. (7) (,) (8) The concept of seeded spread has been discussed extensively elsewhere, sometimes under the rubric of "prionoids" (9), and lies outside the scope of this particular review where we will focus upon PrP (C). From this point the story can now be subdivided into four strands of investigation: (1) pathologic effects of Aß can be mediated by binding to PrP (C), (10) (2) the positioning of endoproteolytic processing events of APP by pathologic (ß-cleavage + γ-cleavage) and non-pathologic (α-cleavage + γ-cleavage) secretase pathways is paralleled by seemingly analogous α- and ß-like cleavage of PrP (C) (Fig. 1) (3) similar lipid raft environments for PrP (C) and APP processing machinery, (11) (-) (13) and perhaps in consequence, overlaps in repertoire of the PrP (C) and APP protein interactors ("interactomes"), (14) (,) (15) and (4) rare kindreds with mixed AD and prion pathologies. (16) Here we discuss confounds, consensus and conflict associated with parameters that apply to these experimental settings.

Amyloid ß (Aß) peptide directly activates amylin-3 receptor subtype by triggering multiple intracellular signaling pathways.

The two age-prevalent diseases Alzheimer disease and type 2 diabetes mellitus share many common features including the deposition of amyloidogenic proteins, amyloid ß protein (Aß) and amylin (islet amyloid polypeptide), respectively. Recent evidence suggests that both Aß and amylin may express their effects through the amylin receptor, although the precise mechanisms for this interaction at a cellular level are unknown. Here, we studied this by generating HEK293 cells with stable expression of an isoform of the amylin receptor family, amylin receptor-3 (AMY3). Aß1-42 and human amylin (hAmylin) increase cytosolic cAMP and Ca(2+), trigger multiple pathways involving the signal transduction mediators protein kinase A, MAPK, Akt, and cFos. Aß1-42 and hAmylin also induce cell death during exposure for 24-48 h at low micromolar concentrations. In the presence of hAmylin, Aß1-42 effects on HEK293-AMY3-expressing cells are occluded, suggesting a shared mechanism of action between the two peptides. Amylin receptor antagonist AC253 blocks increases in intracellular Ca(2+), activation of protein kinase A, MAPK, Akt, cFos, and cell death, which occur upon AMY3 activation with hAmylin, Aß1-42, or their co-application. Our data suggest that AMY3 plays an important role by serving as a receptor target for actions Aß and thus may represent a novel therapeutic target for development of compounds to treat neurodegenerative conditions such as Alzheimer disease.

Neuronal receptors as targets for the action of amyloid-beta protein (Aß) in the brain.

Accumulation of neurotoxic soluble amyloid-beta protein (Aß) oligomers in the brains of patients with Alzheimer disease (AD) and their role in AD pathogenesis have emerged as topics of considerable interest in recent years. Soluble Aß oligomers impair synaptic and neuronal function, leading to neurodegeneration that is clinically manifested by memory and cognitive dysfunction. The precise mechanisms whereby Aß oligomers cause neurotoxicity remain unknown. Emerging insights into the mechanistic link between neuronal receptors and soluble Aß oligomers highlight the potential role of these receptors in Aß-mediated neurotoxicity in AD. The current review focuses on studies describing interactions between soluble Aß oligomers and neuronal receptors, and their role in AD pathogenesis. Furthermore, these studies provide insight into potential therapies for AD using compounds directed at putative target receptors for the action of Aß in the central nervous system. We focus on interactions of Aß with subtypes of acetylcholine and glutamatergic receptors. Additionally, neuronal receptors such as insulin, amylin and receptor for advanced glycation end products could be potential targets for soluble Aß-oligomer-mediated neurotoxicity. Aß interactions with other receptors such as the p75 neurotrophin receptors, which are highly expressed on cholinergic basal forebrain neurons lost in AD, are also highlighted.

ß-Amyloid protein (Aß) and human amylin regulation of apoptotic genes occurs through the amylin receptor.

Deposition of amyloid-beta (Aß) protein, a 39-43 amino acid peptide, in the brain is a major pathological feature of Alzheimer's disease (AD). We have previously provided evidence that in primary cultures of rat basal forebrain and human fetal neurons (HFNs), neurotoxic effects of oligomeric Aß are expressed through the amylin receptor. In this study, we utilized RT-PCR arrays to compare RNA expression levels of 84 markers for pro and anti- apoptotic signalling pathways following exposure of HFNs to either Aß(1-42) (20 µM) or human amylin (2 µM). Oligomeric Aß(1-42) or human amylin was applied to HFNs alone or after pre-treatment of cultures with the amylin receptor antagonist, AC253. Changes in RNA levels were then quantified and compared to each other in order to identify increases or decreases in gene expression of apoptotic markers. Applications of Aß(1-42) or human amylin, but not the inactive inverse sequence Aß(42-1) or rat amylin, resulted in a time-dependent marked increase in mediators of apoptosis including a 10- to 30-fold elevations in caspases 3, 6, 9, BID and XIAP levels. Amylin receptor antagonists, AC253 (10 µM) or AC187 (10 µM), significantly attenuated the induction of several pro-apoptotic mediators up-regulated following exposure to Aß(1-42) or human amylin and increased the expression of several anti-apoptotic markers. These data allow us to identify key elements in the Aß-induced apoptosis that are blocked by antagonism of the amylin receptor and further support the potential for amylin receptor blockade as a potential therapeutic avenue in AD.

Aß inhibition of ionic conductance in mouse basal forebrain neurons is dependent upon the cellular prion protein PrPC.

Current therapies for Alzheimer's disease (AD) address a loss of cholinergic neurons, while accumulation of neurotoxic amyloid ß (Aß) peptide assemblies is thought central to molecular pathogenesis. Overlaps may exist between prionopathies and AD wherein Aß oligomers bind to the cellular prion protein PrP(C) and inhibit synaptic plasticity in the hippocampus (Laurén et al., 2009). Here we applied oligomeric Aß to neurons with different PrP (Prnp) gene dosage. Whole-cell recordings were obtained from dissociated neurons of the diagonal band of Broca (DBB), a cholinergic basal forebrain nucleus. In wild-type (wt) mice, Aß1₋42 evoked a concentration-dependent reduction of whole-cell outward currents in a voltage range between -30 and +30 mV; reduction occurred through a combined modulation of a suite of potassium conductances including the delayed rectifier (I(K)), the transient outward (I(A)), and the iberiotoxin-sensitive (calcium-activated potassium, I(C)) currents. Inhibition was not seen with Aß42₋1 peptide, while Aß1₋42-induced responses were reduced by application of anti-PrP antibody, attenuated in cells from Prnp°/⁺ hemizygotes, and absent in Prnp°/° homozygotes. Similarly, amyloidogenic amylin peptide depressed DBB whole-cell currents in DBB cells from wt mice, but not Prnp°/° homozygotes. While prior studies give broad support for a neuroprotective function for PrP(C), our data define a latent pro-pathogenic role in the presence of amyloid assemblies.