Unintended effects of cardiovascular drugs on the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is rapidly becoming one of the leading causes of disability and mortality in the elderly. As life-expectancy increases, an increasing number of people will rely on modern medicines to treat age-associated disorders. Among these medications, some might benefit, while others might exacerbate, the pathogenesis of AD. We screened 1,600 FDA approved drugs for ß-amyloid (Aß)-modifying activity and identified drugs that can potentially influence amyloid precursor protein processing. In this study, we focused on cardiovascular drugs and demonstrated that some hypertensive medication can differentially modulate Aß, both in vitro and in vivo. Our study suggests that some commonly prescribed drugs might exert unintended effects and modulate AD and provides the basis for continuing investigation of the role of individual drugs on a case-by-case basis. This line of investigation will lead to the identification of common medications that are potentially beneficial or detrimental to AD as a reference for physicians to consider when prescribing the most appropriate drugs for their patients, particularly for treating chronic disorders among the growing geriatric population.

Brain-targeted proanthocyanidin metabolites for Alzheimer's disease treatment.

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 supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer's disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric forms. In this study, we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ∼400 nM. Most importantly, we report for the first time that a biosynthetic epicatechin metabolite, 3'-O-methyl-epicatechin-5-O-ß-glucuronide (3'-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3'-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia.

Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) is a principal regulator of mitochondrial biogenesis and oxidative metabolism. RESULTS: In this study, we examined whether PGC-1α plays a protective role in ALS by using a double transgenic mouse model where PGC-1α is over-expressed in an SOD1 transgenic mouse (TgSOD1-G93A/PGC-1α). Our results indicate that PGC-1α significantly improves motor function and survival of SOD1-G93A mice. The behavioral improvements were accompanied by reduced blood glucose level and by protection of motor neuron loss, restoration of mitochondrial electron transport chain activities and inhibition of stress signaling in the spinal cord. CONCLUSION: Our results demonstrate that PGC-1α plays a beneficial role in a mouse model of ALS, suggesting that PGC-1α may be a potential therapeutic target for ALS therapy.

Preclinical study of dimebon on ß-amyloid-mediated neuropathology in Alzheimer's disease.

BACKGROUND: Dimebon is a retired non-selective antihistamine drug currently being investigated as a therapeutic agent for the treatment of Alzheimer's disease (AD). Results from several completed clinical trials are mixed and contradictory. Proper interpretations of these clinical observations, as well as future development of dimebon in AD treatment are complicated by the lack of concrete information on the mechanisms by which dimebon might benefit AD. RESULTS: The present studies are designed specifically to assess whether dimebon might modulate ß-amyloid (Aß)-mediated responses which are central to the development and progression of AD dementia. We found that dimebon is bioavailable in the brains of mice following oral administration. AD mice chronically treated with dimebon exhibited a trend of improvement in spatial memory function without affecting the levels of total Aß as well as soluble oligomeric Aß in the brain. The same trend of behavior improvement is also seen in wild type animals chronically treated with dimebon. CONCLUSION: Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function independent of Alzheimer's disease-type Aß-related mechanisms or global energy metabolism in the brain. Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington's disease, or in the aging population. Additional studies will be necessary to clarify the mechanisms by which dimebon might directly or indirectly benefit cognitive function.

Carvedilol as a potential novel agent for the treatment of Alzheimer's disease.

Oligomeric ß-amyloid (Aß) 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 ß-adrenergic receptor blocker, significantly attenuates brain oligomeric ß-amyloid content and cognitive deterioration in 2 independent AD mouse models. We found that carvedilol treatment significantly improved neuronal transmission, and that this improvement was associated with the maintenance of number of the less stable "learning" thin spines in the brains of AD mice. Our novel observation that carvedilol interferes with the neuropathologic, biochemical, and electrophysiological mechanisms underlying cognitive deterioration in AD supports the potential development of carvedilol as a treatment for AD.

Mitochondrial bioenergetics is defective in presymptomatic Tg2576 AD mice.

Alzheimer's disease (AD) is an age-related dementia, with the pathological hallmarks of neuritic plaques and neurofibrillary tangles, brain atrophy and loss of synaptic terminals. Dysfunctional mitochondrial bioenergetics is implicated as a contributing factor to the cognitive decline observed in AD. We hypothesized that, in the presence of the AD neurotoxic peptide beta-amyloid, mitochondrial respiration is impaired early in synaptic terminals, which are vital to cognitive performance, preferentially in cognitive centers of the brain. We compared oxygen consumption in synaptosomal and perikaryal mitochondria prepared from the cerebral cortex and cerebellum of wild type (WT) and AD transgenic Tg2576 mice. Compared to WT mice, Tg2576 mice showed decreased mitochondrial respiration in the cerebral cortex specifically in synaptosomal fraction, while the perikaryal mitochondria were unaffected. Neither mitochondrial fraction was affected in the cerebellum of Tg2576 mice as compared to WT. The occurrence of a bioenergetic defect in synaptic terminals of mice overexpressing mutant beta-amyloid, in particular in an area of the brain important to cognition, points to an early role of mitochondrial defects in the onset of cognitive deficits in AD.

POTENTIAL APPLICATION OF GRAPE DERIVED POLYPHENOLS IN HUNTINGTON'S DISEASE.

Huntington's disease (HD) is a progressive neurodegenerative disorder associated with selective neuronal cell death. Abnormal aggregation of huntingtin protein with polyQ expansion has been shown to be causally linked to HD. Grape seed polyphenolic extract (GSPE) is a natural compound that has previously been shown to interfere with aggregations of proteins involved in neurological disorders, such as amyloid beta peptides (Aß) and Tau protein. In this study we found that GSPE treatment significantly inhibits polyQ aggregation in phaeochromocytoma (PC)-12 cell line containing an ecdysone-inducible protein comprising the first 17 amino acid of huntingtin plus 103 glutamines fused with enhanced GFP. In vivo feasibility studies using the Q93httexon1 drosophila model of HD, we extended our in vitro evidence and found that flies fed with GSPE had a significantly improved lifespan compared to the control flies. Using the R6/2 rodent model of HD, we found that oral administration of 100 mg/kg/day GSPE (equivalent to 500mg per day in human) significantly attenuated the motor skill decay as well as extended the lifespan in the R6/2 mice relative to vehicle-control mice. Collectively, our studies strongly suggest that GSPE might be able to modulate the onset and/or progression of HD.

Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease.

Recent epidemiological evidence suggests that some antihypertensive medications may reduce the risk for Alzheimer disease (AD). We screened 55 clinically prescribed antihypertensive medications for AD-modifying activity using primary cortico-hippocampal neuron cultures generated from the Tg2576 AD mouse model. These agents represent all drug classes used for hypertension pharmacotherapy. We identified 7 candidate antihypertensive agents that significantly reduced AD-type beta-amyloid protein (Abeta) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Abeta peptides into high-molecular-weight (HMW) oligomeric peptides, known to be involved in cognitive deterioration. We found that preventive treatment of Tg2576 mice with valsartan significantly reduced AD-type neuropathology and the content of soluble HMW extracellular oligomeric Abeta peptides in the brain. Most importantly, valsartan administration also attenuated the development of Abeta-mediated cognitive deterioration, even when delivered at a dose about 2-fold lower than that used for hypertension treatment in humans. These preclinical studies suggest that certain antihypertensive drugs may have AD-modifying activity and may protect against progressive Abeta-related memory deficits in subjects with AD or in those at high risk of developing AD.

Teneurin proteins possess a carboxy terminal sequence with neuromodulatory activity.

We have previously shown that a bioactive neuropeptide-like sequence is present at the carboxy-terminus of the teneurin transmembrane proteins. We have subsequently called this peptide 'teneurin C-terminal associated peptide' (TCAP). The sequence encodes a peptide 40 or 41 amino acids long flanked by a cleavage motif on the amino terminus and an amidation motif on the carboxy terminus, characteristic of bioactive peptides. This sequence is highly conserved in all vertebrates. A TCAP-like sequence is encoded by each of the four teneurin genes. We have therefore examined the neurological role TCAP-1 may play in mice and rats. In situ hybridization studies showed that the teneurin-1 mRNA containing the TCAP-1 sequence is expressed in regions of the forebrain and limbic system regulating stress and anxiety. A synthetic version of amidated mouse/rat TCAP-1 was prepared by solid-phase synthesis and used to investigate the in vitro and in vivo activity. TCAP-1 induces a dose-dependent change in cAMP accumulation and MTT activity in immortalized mouse neurons. Administration of synthetic TCAP-1 into the basolateral amygdala significantly increases the acoustic startle response in low-anxiety rats and decreases the response in high-anxiety animals in a dose-dependent manner. When 30 pmol TCAP-1 is administered into the lateral ventricles each day for 5 days, the sensitization of the rats to the acoustic startle response is abolished. These data indicate that TCAP may possess functions that are independent of the teneurin proprotein and together, the teneurins and TCAP, may represent a novel system to regulate neuronal function and emotionality.

Cloning and characterization of teneurin C-terminus associated peptide (TCAP)-3 from the hypothalamus of an adult rainbow trout (Oncorhynchus mykiss).

Neuropeptides that evolved early in metazoan evolution may possess much larger networks of paralogous genes than later evolving peptides due to the increased exposure to gene and genomic duplication events. The corticotropin-releasing factor family of peptides, which also include invertebrate CRF-like peptides, are a candidate group that appear to have an early origin. We have attempted to find additional paralogous genes to the CRF family by doing a low-stringency screen of a rainbow trout hypothalamic cDNA library using a hamster urocortin probe. A clone was identified that represented the rainbow trout ortholog of teneurin-3. The C-terminal region of the last exon teneurin transmembrane protein gene possesses a neuropeptide-like sequence with a primary structure similarity to the corticotropin-releasing factor family of peptides. We have called this sequence teneurin C-terminal associated peptide (TCAP). The predicted peptide is 40 residues long and possesses an expected pyroglutamyl residue in the first position and an amidated carboxy terminus. A synthetic version of the rainbow trout (rt) TCAP-3 is potent at increasing the concentration of cAMP and stimulating proliferation in a neuronal cell line. The synthetic peptide can also either increase or decrease the expression of the teneurin-1 gene, depending upon its concentration. The teneurin/TCAP system may represent a novel and highly conserved regulatory signalling system in the vertebrate brain.

Effects of oral administration of type II collagen on adjuvant arthritis in rats and its mechanisms.

OBJECTIVE: To investigate the effects of oral administration of type II collagen (CII) on adjuvant arthritis (AA) in rats and its mechanisms, and to compare the effects of CII with those of the Chinese traditional medicine Tripterygium Polyglycoside administered similarly. METHODS: Arthritis was induced in rats by immunization using Freund's complete adjuvant (FCA). After feeding rats either soluble CII or Tripterygium Polyglycoside, changes in degree of articular swelling and articular histological findings were observed in AA rats. Some correlative immunological indexes were measured, including delayed type hypersensitivity (DTH) reaction, anti-collagen and anti-Mycobacterium tuberculosis (MT) antibody in serum, and levels of IFN-gamma and TNF-alpha in articular steep in rats. RESULTS: Oral administration of CII was able to alleviate both distinctly articular and general symptoms in AA rats, suppress synovium hyperplasia and inflammatory cells infiltration in arthrosis capsule. The effects brought about by CII were stronger than those by Tripterygium Polyglycoside. Oral administration of CII inhibited antigen-specific immune response, such as DTH and antibody reaction to CII. In addition, the expression of IFN-gamma and TNF-alpha in joints were locally downregulated. CONCLUSIONS: The therapeutic effect of oral administration of CII is obvious on adjuvant arthritis in rats. Its remedial mechanisms are likely related to the downregulation of both IFN-gamma and TNF-alpha, and the suppression of cell immunity.