Microglia and neuroprotection: implications for Alzheimer's disease

The first part of this paper summarizes some of the key observations from experimental work in animals that support a role of microglia as neuroprotective cells after acute neuronal injury. These studies point towards an important role of neuronal–microglial crosstalk in the facilitation of neuroprotection. Conceptually, injured neurons are thought to generate rescue signals that trigger microglial activation and, in turn, activated microglia produce trophic or other factors that help damaged neurons recover from injury. Against this background, the second part of this paper summarizes recent work from postmortem studies conducted in humans that have revealed the occurrence of senescent, or dystrophic, microglial cells in the aged and Alzheimer's disease brain. These findings suggest that microglial cells become increasingly dysfunctional with advancing age and that a loss of microglial cell function may involve a loss of neuroprotective properties that could contribute to the development of aging-related neurodegeneration.     

Neurogenesis in the adult brain: implications for Alzheimer's disease

The function of neurogenesis in the adult brain is still unknown. Interventions such as environmental enrichment and exercise impinge on neurogenesis, suggesting that the process is regulated by experience. Conversely, a role for neurogenesis in learning has been proposed through 'cellular plasticity', a process akin to synaptic plasticity but operating at the network level. Although neurogenesis is stimulated by acute injury, and possibly by neurodegenerative processes such as Alzheimer's disease (AD), it does not suffice to restore function. While the role and direction of change in the neurogenic response at different stages of AD is still a matter of debate, it is possible that a deficit in neurogenesis may contribute to AD pathogenesis since at least one of the two regions ostensibly neurogenic in the adult human brain (the subgranular zone of the dentage gyrus and the ventriculo-olfactory neurogenic system) support high-level functions affected in early AD (associative memory and olfaction respectively). The age of onset and the rate of progression of sporadic forms of AD are highly variable. Sporadic AD may have a component of insufficient neurogenic replacement or insufficient neurogenic stimulation that is correlated with traits of personal history; the rate of neurogenesis and the survival of replicating progenitors is strongly modified by behavioral interventions known to impinge on the rate of neurogenesis and the probability of survival of newly born neurons--exercise, enriched experience, and learning. This view is consistent with epidemiological data suggesting that higher education and increased participation in intellectual, social and physical aspects of daily life are associated with slower cognitive decline in healthy elderly ("cognitive reserve") and may reduce the risk of AD. Although neurogenesis can be modulated exogenously by growth factors, stimulation of neurogenesis as a mean to treat neurodegeneration is still for the most part speculative. Moreover, it is possible that different roles of neurogenesis during the course of AD are dictated by the degree of permissibility of the environment in which the process is taking place. A unique opportunity may exist in which the therapeutic stimulation of neurogenesis might contribute to functional 'repair' of the adult diseased brain, before damage to whole neuronal networks has ensued. In spite of the considerable gaps in our knowledge of neurogenesis, and of the considerable limitations that will need to be overcome before we can intervene in the process, that new neurons are added continuously to the adult mammalian brain is a discovery that has already changed the way we think about neurobiology, and may soon change the way we understand and approach neurodegenerative diseases such as AD.     

Mercaptopropionaldehyde from homocysteine: implications for Alzheimer's disease

There has been evidence for a causal relationship between homocysteine and Alzheimer's disease for several years but the mechanism is unclear. In vivo, some homocysteine is converted to the thiolactone. This report describes a novel reaction between homocysteine thiolactone and dehydroascorbic acid in which the homocysteine thiolactone is converted to 3-mercaptopropionaldehyde. This product is shown to react with proteins causing their precipitation (probably by cross-linking). The two reactions are extremely facile and appear to be physiologically compatible suggesting a mechanism by which homocysteine may promote the deposition of proteins in nerve cells as amyloid plaques and fibrillary tangles.     

Acetylcholinergic neurotransmission and the beta-amyloid cascade: implications for Alzheimer's disease

Alzheimer's disease is characterized by both decreases in acetylcholinergic neurotransmission and increases in beta-amyloid accumulation. Currently, available clinical psychopharmacologic treatment is focused on increasing acetylcholinergic neurotransmission, whereas no clinical treatments to directly reduce beta-amyloid accumulation are available. Cholinesterase inhibitors improve cognition, certain neuropsychiatric symptoms and functional impairment in patients with mild-to-moderate Alzheimer's disease, and it is believed that this is mainly symptomatic treatment. However, this review discusses various levels of interaction between acetylcholinergic neurotransmission and the beta-amyloid cascade, which suggest that some specific acetylcholinergic treatments may reduce beta-amyloid accumulation, and therefore may slow disease progression over the long term. Various suggestions are made on how such potential disease-modifying effects could be studied in the future.     

Kynurenine metabolism in Alzheimer's disease

Summary. L-kynurenine (L-KYN) serves as a substrate for the synthesis of neurotoxic 3-OH-kynurenine (3-OH-KYN) and neuroprotective kynurenic acid (KYNA). KYNA is able to interact with ionotropic excitatory amino acid receptors that are involved in a variety of neurodegenerative disorders. The purpose of the present study was to investigate the biosynthetic machinery of KYNA in several regions of Alzheimer's disease (AD) brain. The endogenous levels of L-KYN, 3-OH-KYN and KYNA in frontal cortex, caudate nucleus, putamen, hippocampus, and cerebellum of 11 autopsy confirmed cases of AD and 13 age-matched controls were analyzed. Subsequently, the activity of two proteins responsible for the production of KYNA, kynurenine aminotransferases I and II (KAT I and KAT II), was investigated. There was a trend for a decrease of L-KYN and 3-OH-KYN in all examined regions of AD brain, as compared to controls. However, KYNA was increased significantly in the putamen and caudate nucleus of AD, by 192 and 177%, respectively. In other areas of AD brain only a minor increase of KYNA was present. Elevated KYNA in the caudate nucleus and putamen correlated with a significant increase of KAT I activities in both nuclei – 157 and 147%, respectively. A minor increase of KAT II was measured only in the caudate nucleus of AD subjects. Kinetic analysis of KAT I and II performed in the caudate nucleus of AD patients revealed a marked increase of V_max, by 207 and 274% of controls, respectively. K_m value for L-KYN using pyruvate as amino acceptor was significantly higher for KAT II (247% of controls). The present data indicate an elevated kynurenine metabolism in AD brain. A marked increase of KYNA in the caudate nucleus and putamen may compensate the hyperactivity of the striato-frontal loop in AD brains. Blockade of NMDA receptors by KYNA may be responsible for impaired memory, learning and cognition in AD patients. Received May 26, 1998; accepted September 9, 1998     

Endocannabinoid metabolism and Alzheimer’s disease

Alzheimer’s disease(AD)is the most common cause of dementia in the elderly.Unfortunately,there are no effective therapies currently available for prevention and treatment of AD.As it is clear now,the etiology of AD is multifactorial and complex.This means that development of AD is linked to multiple mechanisms or signaling pathways and that a single-target therapy for AD is likely insufficient to achieve therapeutic goals.Therefore,an ideal therapy for AD should be able to modify the disease through multiple signaling pathways.2-Arachidonoylglycerol(2-AG)is an endogenous cannabinoid(endocannabinoid)displayinganti-inflammator y a n d neuroprotective properties,while its metabolites are arachidonic acid(AA)and AA-derived prostaglandins and leukotrienes,which are proinflammatory and neurotoxic(Figure 1).     

Xenobiotic metabolism in Alzheimer's disease

Using 5 methods, we assessed the ability of patients with a clinical diagnosis of Alzheimer's disease (AD) to handle xenobiotics. Patients with AD, compared with controls, have reduced sulfoxidation of the probe drug S-carboxymethyl-L-cysteine; they also form less of the sulfate conjugate of acetaminophen. In addition, they have lower activity of the enzyme thiolmethyltransferase. In contrast, the capacity to oxidize debrisoquin and to acetylate sulfamethazine was normal. These findings suggest that a major risk factor for the development of AD is a skewed capacity for xenobiotic metabolism especially of compounds containing sulfur.     

Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease with major clinical hallmarks of memory loss, dementia, and cognitive impairment. Neuroinflammation is involved in the onset of several neurodegenerative disorders. Astrocyte is the most abundant type of glial cells in the central nervous system (CNS) and appears to be involved in the induction of neuroinflammation. Under stress and injury, astrocytes become astrogliotic leading to an upregulation of the expression of proinflammatory cytokines and chemokines, which are associated with the pathogenesis of AD. Cytokines and related molecules play roles in both neuroprotection and neurodegeneration in the CNS. During early AD pathogenesis, amyloid beta (Aβ), S100B and IL-1β could bring about a vicious cycle of Aβ generation between astrocytes and neurons leading to chronic, sustained and progressive neuroinflammation. In advanced stages of AD, TRAIL secreted from astrocytes have been shown to bind to death receptor 5 (DR5) on neurons to trigger apoptosis in a caspase-8-dependent manner. Furthermore, astrocytes could be reactivated by TGFβ1 to generate more Aβ and to undergo the aggravating astrogliosis. TGFβ2 was also observed to cooperate with Aβ to cause neuronal demise by destroying the stability of lysosomes in neurons. Inflammatory molecules can be either potential biomarkers for diagnosis or target molecules for therapeutic intervention. Understanding their roles and their relationship with activated astrocytes is particularly important for attenuating neuroinflammation in the early stage of AD. The main purpose of this review is to provide a comprehensive insight into the role of astrocytes in the neuroinflammatory pathogenesis of AD.     

Ionic conductance determinants of synaptic memory nets and their implications for Alzheimer's disease.

Electrical and chemical signals representing macroscopic "perturbations" in brain networks engage large numbers of transient "microscopic" ionic channel fluctuations in producing long-lasting changes of conductance (and thus potential). Repeated electrical and chemical signals that occur during associative training of living organisms (from mollusc to mammal) can cause ionic conductance changes lasting from days to many weeks. If a stimulus pattern reoccurs with sufficient frequency, voltage-dependent K(+) conductances-responsible for both synaptic and intrinsic membrane currents-become progressively less probabilistic and more deterministic. In effect, more deterministic ion channel functions record in associative memory more deterministic (i.e., higher probability) events in the environment. This memory has been found to be stored within brain networks as ensembles of local dendritic ionic conductance changes distributed throughout brain regions such as the hippocampus and cerebellar cortex. Numerous other studies taken together support the hypothesis that distributed dendritic loci store associative memory, do not involve long-term potentiation, are also loci for Alzheimer's disease (AD) pathophysiology, and can contribute to, if not be responsible for, early memory loss in clinically manifest AD. J. Neurosci. Res. 58:24-32, 1999. Published 1999 Wiley-Liss, Inc.     

Anti-inflammatory therapy for Alzheimer's disease: implications of the prednisone trial

The inflammatory hypothesis of Alzheimer's disease (AD), which is supported both by basic laboratory evidence and epidemiological studies, suggests that treatment with anti-inflammatory drugs may reduce the risk or slow the progression of AD. In the first large-scale test of this hypothesis, the Alzheimer's Disease Cooperative Study (ADCS) conducted a randomized placebo-controlled trial of low-dose prednisone treatment in subjects with probable AD. There was no difference in cognitive decline between the prednisone and placebo treatment groups; subjects treated with prednisone showed behavioral decline compared to those in the placebo group. While this study indicates that a low-dose regimen of prednisone is not useful in the treatment of AD, it does not refute the inflammatory hypothesis; recent evidence supports testing of a number of alternative anti-inflammatory regimens, for prevention and/or treatment of AD. The ADCS has initiated a trial to determine whether treatment with a non-selective non-steroidal anti-inflammatory drug or a selective cyclooxygenase-2 inhibitor is effective in slowing the rate of cognitive decline in AD.     

Preserved motor learning in Alzheimer's disease: implications for anatomy and behavior

Learning and retention of 3 types of information were examined in patients with Alzheimer's disease (AD) and in normal controls. While patients were unable to learn series of frequent words and unfamiliar faces, they improved significantly in a motor skill, showing a learning curve similar to controls. Furthermore, no significant loss of the motor skill was evident in a 20 min delay trial. Such dissociation in learning has not been noted previously in AD, although it has been noted in amnesias caused by other disease processes. The results support the existence of two, relatively independent, learning systems related to "declarative" knowledge and "procedural" knowledge. Judging from the pathologic correlates of these amnesias, the declarative knowledge system appears to be associated with corticotemporo/limbic structures, while the procedural system is likely to depend on corticocerebellar/striatal structures. The data also offer additional cognitive correlates for the selective damage to neural systems recently identified in AD.     

Alzheimer's disease: lesions and their progression

Alzheimer disease appears to be a stereotyped mode of reaction of the central nervous system to various types of aggression such as different mutations involving various proteins, trisomy 21 or repeated head trauma as in dementia pugilistica. Rather than a disease, it appears to be a clinicopathological syndrome due to various causes. Lesions may be considered under 3 headings: neurofibrillary pathology, A beta peptide deposits and loss (neuronal and synaptic). Neurofibrillary pathology includes the neurofibrillary tangle, the crown of the senile plaque and the neuropil threads. All those lesions are characterized by the same ultrastructure--i.e. the accumulation of paired helical filaments--and the same immunohistochemistry: they are labelled by antibodies directed against the tau proteins. The amyloid deposits, present in the core of the senile plaque and in the vascular walls, are made of a 40 to 42 amino-acids long peptide, named A beta, derived from the amyloid precursor protein (APP). Antibodies directed against the A beta peptide also label diffuse deposits that are devoid of the tinctorial affinities and of the biochemical properties of amyloid substances. Those diffuse deposits are insufficient to cause dementia since they may be observed in high density in aged people without intellectual deterioration. Neuronal loss occurs after neurofibrillary pathology. The role of the synaptic pathology remains discussed. Besides tau proteins, A beta peptide and APP, several other proteins may play an important role: apolipoprotein E which could act as a chaperone protein, inducing or facilitating the formation of amyloid, presenilins 1 and 2, mutated in some cases of familial Alzheimer disease, alpha-synuclein which is present in the Lewy bodies found in Parkinson disease and in dementia with Lewy bodies. The A beta deposits are diffusely distributed in the cerebral cortex; the neurofibrillary changes have a hierarchical distribution. The progression of the neurofibrillary pathology in the various cortical areas follow a stereotyped sequence that may help to grade the severity of the disease. Progression may take decades. The relations between aging and Alzheimer disease are still poorly understood. Frequency of Alzheimer type lesions in old people could suggest that they are the inevitable burden of age, but this has been discussed.     

Lipid peroxidation in Alzheimer's disease: emphasis on metal-mediated neurotoxicity

Despite the crucial role of redox active metals like copper and iron in central biological reactions, their elevated levels are involved in the pathogenesis of Alzheimer's Disease (AD). Similarly reactive oxygen/nitrogen species (ROS/RNS) produced during normal metabolic activities, specifically oxidative phosphorylation of the cell, are scavenged by antioxidant enzymes like superoxide dismutase (SOD), catalase but impaired metabolic pathways tend to generate elevated levels of these ROS/RNS. Iron, copper, and zinc are some of the metals, which intensify this process and contribute for the pathogenesis of AD. This review summarizes the mechanism of ROS/RNS production and their role in lipid peroxidation. The factors, which make brain vulnerable for lipid peroxidation, have been discussed. It also focuses on possible treatment options and future directions.     

Comparison between Alzheimer's disease and vascular dementia: implications for treatment

Virtually 90% of the elderly with late-onset dementia exhibit neuropathological features consistent with Alzheimer's disease (AD), vascular dementia (VaD) or dementia with Lewy bodies (DLB), alone or in combination. Both AD and DLB reveal extensive senile plaques containing amyloid beta whereas neurofibrillary tangles evident as tau pathology are fewer in DLB, which also bears diffuse cortical Lewy bodies. Interestingly, however, there is considerable overlap between AD and VaD in terms of both risk factors and pathology. Cholinergic deficits are also encountered in VaD, which like AD may respond to cholinergic therapy. Cerebrovascular pathology, ischemic brain damage and autonomic dysregulation resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementias.     

d-serine levels in Alzheimer's disease: implications for novel biomarker development

Alzheimer''s disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.     

Systemic and central immunity in Alzheimer's disease: therapeutic implications

Clinical pharmaceutical trials aimed at modulating the immune system in Alzheimer's Disease have largely focused on either dampening down central proinflammatory innate immunity or have manipulated adaptive immunity to facilitate the removal of centrally deposited beta amyloid. To date, these trials have had mixed clinical therapeutic effects. However, a number of clinical studies have demonstrated disturbances of both systemic and central innate immunity in Alzheimer's Disease and attention has been drawn to the close communication pathways between central and systemic immunity. This paper highlights the need to take into account the potential systemic effects of drugs aimed at modulating central immunity and the possibility of developing novel therapeutic approaches based on the manipulation of systemic immunity and its communication with the central nervous system.