Current Alzheimer Research - Volume 10, Issue 5, 2013

Neuropeptides are found throughout the entire nervous system where they can act as neurotransmitter, neuromodulator or neurohormone. In those functions, they play important roles in the regulation of cognition and behavior. In brain disorders like Alzheimer's disease (AD), where abnormal cognition and behavior are observed, the study of neuropeptides is particularly interesting since altered neuropeptides can function as biomarkers or as targets for new medication. In this article neuropeptides with relevance to AD are listed and their influence on cognitive and behavioral disturbances is discussed. Findings from human cerebrospinal fluid and brain tissue, and AD mouse models are described and related to the pathophysiology and symptomatology of the disease. In the past, clinical trials with neuropeptides have often failed due to insufficient delivery to the brain. Therefore, new strategies to target the brain with peptide drugs are also covered.

Neostriatum is one of the brain areas that are not primarily affected in Alzheimer's disease, according to classic regard of the disease. However, recent data emphasize the involvement of neostriatum, especially the head of the caudate nucleus, in the emergence of characteristic symptoms of the disease. Glutamatergic neurotransmission is a key component of striatal pathways. The present study is focused on glutamate receptors of striatal neurons on human caudate nucleus in normal aging and Alzheimer's disease. Immunohistochemical studies were carried out for N-methyl-D-aspartate receptor subunit 1 (NMDAR1), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit 2 (GluR2) and metabotropic glutamate receptor 5 (mGluR5). Ionotropic receptors (NMDAR1 and GluR2) were found to be expressed by 82% - 93% of striatal neurons with no significant alterations in aging and Alzheimer's disease. On the other hand, metabotropic receptor mGluR5 was found to be expressed by just 40% of striatal neurons in young individuals, with significant intensity variations among the neurons. This percent was increased in elderly individuals and Alzheimer's disease patients to 80% and 92% of striatal neurons, respectively. The up-regulation of mGluR5 both in normal aging and Alzheimer's disease is possibly associated with reorganization of neuronal connections, indicates the complexity of this receptor function and renders quite unpredictable the intervention and treatment of dementia with mGluR5 inhibitors or modulators.

Cholinesterase inhibitors (ChEIs), the mainstay treatment for dementia, have systemic actions that can affect cardiovascular and autonomic nervous system (ANS). Thirty-nine patients with Alzheimer's disease or mixed dementia underwent a comprehensive clinical evaluation, prior to and during ChEIs therapy, including orthostatic challenge, electrocardiogram (EKG) and heart rate variability (HRV) spectral analysis through Holter recordings. ChEIs therapy determined a decrease in supine diastolic blood pressure (BP) and in both diastolic and systolic BP in orthostatic position (79.8 ± 9.0 vs. 76.4 ± 9.3 mmHg, p=0.012; 79.9 ± 11.6 vs. 75.3 ± 9.9, p=0.005 and 144.6 ± 25.8 vs. 137.6 ± 21.1, p=0.020, respectively). Spectral analysis revealed no difference on static HRV components, but, during orthostatic challenge, an increase in LF/HF ratio (2.2±2.4 vs. 4.6±5.9, p=0.011) and a reduction in HF component emerged (1604.3 ± 5610.1 vs. 266.1 ± 525.5, p=0.010). ChEIs showed no influence on EKG parameters or on the occurrence of orthostatic hypotension. Treatment with ChEIs was associated with functional improvement of the ANS behavior and to a decrease in supine DBP and in both orthostatic SBP and DBP.

Immunotherapy against amyloid-β(Aβ) may improve rodent cognitive function by reducing amyloid neuropathology and is being validated in clinical trials with positive preliminary results. However, for a complete understanding of the direct and long-term immunization responses in the aged patient, and also to avoid significant side effects, several key aspects remain to be clarified. Thus, to investigate brain Aβ clearance and Th2 responses in the elderly, and the reverse inflammatory events not found in the immunized rodent, better Alzheimer's disease (AD) models are required. In the aged familiar canine with a Cognitive Dysfunction Syndrome (CDS) we describe the rapid effectiveness and the full safety profile of a new active vaccine candidate for human AD prevention and treatment. In these aged animals, besidesa weak immune system, the antibody response activated a coordinated central and peripheral Aβ clearance, that rapidly improved their cognitive function in absence of any side effects. Our results also confirm the interest to use familiar dogs to develop innovative and reliable therapies for AD.

Alzheimer's disease (AD), the most common human neurodegenerative disease, is characterized pathologically by numerous deposits of amyloid plaques in the brain. Systemic administration of clioquinol (CQ) and inoculation with amyloid-beta42 (Aβ42) vaccines have been demonstrated to significantly inhibit deposits of amyloid in AD brains. However, each of these treatments has also been reported to be neurotoxic. The generation of transgenic mice models of AD has made it possible to study aspects of this disease employing experimental animals. In the present study, we investigated the efficacy and toxicity of CQ and Aβ42 vaccine in a transgenic AD (APP/PS1) mouse model. Our results confirmed that both CQ and Aβ42 vaccine were effective in significantly reducing the deposits of amyloid in the brains of transgenic AD mice. We also report here that systemic CQ induces myelinopathies in the dorsal lateral geniculate nucleus (DLG), which was almost devoid of amyloid plaques and is the primary site of retinal efferent projections via the optic nerve. This is the first report that systemic administration of CQ causes myelinopathies in the central nervous system (CNS) of a transgenic AD mouse model as well as wild-type mice. Inoculation with an Aβ42 vaccine was also found, for the first time, to result in a significant increase in plaque-independent astrocytic hyperplasia in the dorsal part of the lateral septal nucleus (LSD) which was also devoid of plaques, reflecting potential brain inflammatory processes.

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive memory loss. In contrast, accumulating evidence suggests a neuroprotective role of regular exercise in aging associated memory impairment. In this study, we investigated the ability of regular exercise to prevent impairments of short-term memory (STM) and early long-term potentiation (E-LTP) in area CA1 of the hippocampus in a rat model of AD (i.c.v. infusion of 250 pmol/day Aβ1-42 peptides). We utilized behavioral assessment, in vivo electrophysiological recording, and immunoblotting in 4 groups of adult Wistar rats: control, treadmill exercise (Ex), β-amyloid-infused (Aβ), and amyloid-infused/treadmill exercised (Ex/Aβ). Our findings indicated that Aβ rats made significantly more errors in the radial arm water maze (RAWM) compared to all other groups and exhibited suppressed E-LTP in area CA1, which correlated with deleterious alterations in the levels of memory and E-LTP-related signaling molecules including calcineurin (PP2B), brain derivedneurotrophic factor (BDNF) and phosphorylated CaMKII (p-CaMKII). Compared to controls, Ex and Ex/Aβ rats showed a similar behavioral performance and a normal E-LTP with no detrimental changes in the levels of PP2B, BDNF, and p- CaMKII. We conclude that treadmill exercise maybe able to prevent cognitive impairment associated with AD pathology.

Behavioral and Psychological Symptoms in Dementia (BPSD) are also seen in Alzheimer's disease (AD), being agitation and anxiety common symptoms. Since cholinergic agonists used to be the first pharmacological intervention in AD and this neurotransmission system have been related to cognitive and behavioral symptoms in this serious disease, we here address the question of a possible therapeutic role of PNU-282987 (PNU), an alpha7 nicotinic agonist, in motor activity and anxiety-like behaviors in an animal model of AD. On the other hand, since stress is an unavoidable condition in our daily activities, which activates physiological systems and deregulates body's homeostasis, we also evaluated the possible precipitating effects of stress in the onset of behavioral deficits in animals with susceptibility to AD. A dose of 0 or 1 mg/kg of PNU was administered to transgenic mice under restrained stress or not, resulting in 4 experimental groups: SAL, PNU, SAL-STR, PNU-STR. The main goal of this study was to evaluate the possible therapeutic role of PNU- 282987 alpha7 nicotinic agonist in motor activity and anxiety-like behaviors, as well as the possible effects of stress in precipitating the onset of behavioral deficits in animals with susceptibility to AD. The present results suggest a differential effect of stress (p=0.011) and PNU (p= 0.009) on anxiety evaluated in an open field depending on genetic vulnerability. Moreover, PNU seems to reverse stress effects in the same apparatus. This was also observed when a more sensitive task such as the zero maze was used.

The remarkable potentiality of bone marrow-derived mesenchymal stem cells (BM-MSCs) after transplantation to models of neurological disease and injury has been described. We have previously published data confirming the influence of BM-MSCs on β-amyloid (Aβ) deposition in an Alzheimer's disease (AD) mouse model. However, therapeutic approaches in neurological diseases such as AD, including those for BM-MSCs, are increasingly centered on the potential for prophylactic therapy in pro-dromal states where the underlying cause of the disease is apparent but functional deficits are not. In order to investigate whether BM-MSCs could have a beneficial effect in high-risk pre-dementia AD individuals, we treated young AD mice, at an age at which they display neuropathological, but not cognitive features of AD. Following a single intra-cerebral injection of BM-MSCs, interestingly, we found a significant decrease in the cerebral Aβ deposition compared with controls treated with PBS that was sustained up to 2 months post-injection. Expression of dynamin 1 and Synapsin 1, key pre-synaptic proteins associated with synaptic transmission, which are typically decreased in brains of AD patients, were considerably enhanced in the brains of AD mice treated with BM-MSCs and this response was sustained beyond 2 months. These data demonstrate that BM-MSCs produce an acute reduction in Aβ deposits and facilitate changes in key proteins required for synaptic transmission. These findings suggest that BM-MSC transplantation warrants further investigation as a potential therapy for early intervention in pro-dromal AD.

BRI2, a protein mutated in Familial British and Familial Danish Dementias, interacts with Amyloid Precursor Protein (APP) and reduces the levels of secreted APPβ (sAPPβ), which derives from APP cleavage by β-secretase (BACE1). Exploring the mechanisms of this effect, we obtained data that BRI2 decreases the cellular levels of BACE1 thus reducing the β-cleavage of APP. Deletion of N-terminal cytoplasmic or C-terminal extracellular sequences of BRI2 neither affected its interaction with BACE1 or APP (Fotinopoulou et al., 2005) nor the reduction in the levels of BACE1 and sAPPβ. These results suggest that BRI2 may prevent access of BACE1 to APP and the BRI2/BACE1 interaction may mediate the reduction in BACE1 levels. In support, BRI2 expression induced lysosomal but not proteasomal degradation of BACE1. In parallel, BRI2 expression was also found to reduce BACE1 mRNA levels by 50%. This study adds novel information regarding the mechanism by which BRI2 affects APP processing and BACE1 levels.

There is a clear need of dietary recommendations or guidelines at both population and/or individual levels, to prevent the Alzheimer's disease or reduce its symptoms. Though data from cellular and animal models of Alzheimer's disease indicate that dietary lipids ameliorate cognitive deficits or neuropathology associated with this disease. However, the data from the present dietary studies are not standardized. Most dietary research in Alzheimer's disease has not examined and compared the differential effects of each fatty acid with other dietary nutrients. Nutrients, particularly different types of fatty acids, absorb, metabolize, and interact with other lipid or nutrients differently in animals and humans with compromised neurological status. Studies in animals and tissue culture should consider such limitations to predict a better response in patients with Alzheimer's disease. The present commentary emphasizes the significance of examining composite lipids/nutrients rather than single fatty acid or nutrient. This report also provides a brief overview of the key factors need to be considered while planning in-vitro, in-vivo or clinical experiments on the effects of dietary fatty acids on Alzheimer's disease. It is to hope that keeping these considerations in mind more judicious use of dietary regimens will speed up the progress of dietary research into the prevention of Alzheimer's disease.

Background: Previous research indicates that persons with chronic obstructive pulmonary disease (COPD) and asthma may have more cognitive impairment compared to persons without these diseases. However, there are no previous studies regarding long-term effects of these diseases on the risk of clinically diagnosed mild cognitive impairment (MCI) and dementia. We examined the association between midlife and late-life self-reported COPD and asthma and the lifelong risk of cognitive impairment (MCI/dementia) in a population-based study with a follow-up of over 25 years. Methods: Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study includes 2000 participants who were randomly selected from four separate, population-based samples originally studied in midlife (1972, 1977, 1982 or 1988). Re-examinations were carried out in 1998 and 2005-8 (N=1511, 75.6 %) during which 172 persons were diagnosed with MCI and 117 with dementia. Results: Midlife COPD (HR 1.85, 95% CI 1.05 – 3.28), asthma (HR 1.88, 95% CI 0.77 – 4.63) and both pulmonary diseases combined (HR 1.94, 95% CI 1.16 – 3.27) increased the later risk of cognitive impairment even after full adjustments. However, pulmonary diseases diagnosed later in life seemed to be inversely related to cognitive impairment (fully adjusted model for both pulmonary diseases combined HR 0.42, 95% CI 0.19 – 0.93). Conclusions: In this population-based study, with more than 25 years of follow-up, midlife COPD and asthma were associated with an almost two-fold risk of MCI and dementia later in life. Pulmonary diseases diagnosed later in life seemed to have an inverse relationship with cognitive impairment probably reflecting survival bias.