Molecular and cellular pathways towards and away from Alzheimers disease

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Mark P. Mattson1

Research in my laboratory is aimed at understanding the factors that determine whether neurons thrive or degenerate during aging ( lns/index.html). Our approach is to elucidate molecular and cellular mechanisms that regulate neuronal plasticity and survival, in the contexts of brain development and aging, and to determine if and how these mechanisms are altered in neurodegenerative disorders. We are particularly interested in signaling and metabolic pathways that are common to multiple neurodegenerative disorders (Fig. 1). Here I summarize some of

Alzheimer Disease Biological Pathways

Fig. 1. Although genetic and environmental factors that lead to neuronal dysfunction and death may differ among neurodegenerative disorders, neurons suffer similar consequences (many of which occur during normal aging), including oxidative stress, energy deficits, perturbed ion homeostasis and accumulation of dysfunctional proteins

Fig. 1. Although genetic and environmental factors that lead to neuronal dysfunction and death may differ among neurodegenerative disorders, neurons suffer similar consequences (many of which occur during normal aging), including oxidative stress, energy deficits, perturbed ion homeostasis and accumulation of dysfunctional proteins

1 Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD, 21224

the findings from my laboratory during the past three decades that have contributed to an understanding of the pathogenesis of Alzheimer's disease (AD), and to its prevention and treatment. The findings described below help to place key discoveries in other laboratories in the areas of genetics, amyloid and tau biology (Selkoe and Schenk 2003; Forman et al. 2004; Hardy 2004; Dermaut et al. 2005) within the broader context of mechanisms of aging, neuronal plasticity and cell death (Mattson 2004).

Two examples of concepts that have arisen from our research are 1) the same cellular signaling mechanisms that regulate the formation of neuronal circuits during development of the nervous system are intimately involved in the pathogenesis of neurodegenerative disorders, and 2) the calcium ion is a key regulator of neuronal plasticity and survival, and disruption of cellular calcium homeostasis plays a pivotal role in neuronal dysfunction and death in both acute and chronic neurodegenerative conditions. One of our early findings relevant to AD was that glutamate, the major excitatory neurotransmitter in the central nervous system, plays an essential role in sculpting the formation of neuronal circuits by precisely regulating dendrite outgrowth and synaptogenesis (Mattson et al. 1989). We established that glutamate regulates the architecture of neurons by activating receptors linked to calcium influx and that calcium, in turn, controls the state of polymerization of actin filaments and microtubules, thereby controlling growth cone behaviors. We also found that overactivation of glutamate receptors can cause neuritic degeneration and cytoskeletal alterations similar to those seen in neurons that degenerate in AD (Mattson 1990). In subsequent studies, we showed that neurotrophic factors can modify the effects of neurotransmitters on neurite outgrowth, synaptogenesis and cell survival, and that this is accomplished by regulation of the expression of genes that encode proteins that regulate cellular calcium homeostasis. The latter findings opened a new area of investigation in the neuroscience field, namely, the functions of neurotrophic factors in synaptic plasticity. Our work on neurotrophic factors (Cheng and Mattson 1991) has also led to clinical trials of neurotrophic factors in human patients, with a specific example being a trial of fibroblast growth factor in stroke patients.

Our research has increased understanding of the biochemical cascades responsible for neuronal dysfunction and death in AD. One example is our investigations into the links between oxidative stress and alterations in cellular ion homeostasis. It had been recognized that oxidative stress was involved in neurodegenerative disorders, but the causes of the oxidative stress and the specific ways in which oxidative stress results in synaptic dysfunction and selective neuronal degeneration were unknown. We established that amyloid beta-peptide (Ap) induces oxyradical production, resulting in membrane lipid peroxidation in neurons. These effects of Ap on the plasma membrane destabilize neuronal calcium homeostasis and render neurons vulnerable to excito-toxicity (Mattson et al. 1992). We showed that an aldehyde called 4-hydroxynonenal is liberated from peroxidized lipids and covalently modifies membrane ion- motive ATPases and glucose and glutamate transporters, impairing their function and thereby disrupting cellular calcium homeoastasis and causing ATP depletion (Mark et al. 1995, 1997). Moreover, we showed that this same lipid peroxidation cascade contributes to the degeneration of neurons in other neurodegenerative disorders, including stroke and amyotrophic lateral sclerosis. We also found that more subtle levels of membrane lipid peroxidation can impair coupling of membrane receptors to GTP-binding proteins, resulting in impaired synaptic transmission. This work established a previously unrec-

Molecular and cellular pathways towards and away from Alzheimer's disease 373

ognized link between oxidative stress and disruption of cellular calcium homeostasis in AD. We also identified several signaling pathways as being capable of protecting neurons from being damaged and killed by Ap, with the transcription factor NF- kB being a key target of several such neuroprotective signaling pathways (Mattson and Meffert 2006).

More recently, we have revealed mechanistic links between oxidative stress, perturbed membrane lipid metabolism and neuronal death in AD. We found that alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients result in accumulation of long-chain ceramides and cholesterol (Cutler et al. 2004). Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to Ap induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with alpha- tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by Ap. Our findings suggest a sequence of events in the pathogenesis of AD in which Ap induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.

Although the normal function of the amyloid precursor protein (APP) is not yet established, we have provided evidence that the a-secretase-derived form of APP (sAPPa) regulates neuronal excitability, synaptic plasticity and neuronal survival. Using whole cell perforated patch and single channel patch clamp analysis of hippocampal neurons, we showed that sAPPa suppresses action potentials and hyperpolarizes neurons by activating high conductance, potassium channels (Furukawa et al. 1996). Activation of potassium channels mediates the ability of the sAPPa to decrease intracellular calcium. In studies of hippocampal slices, we went on to show that sAPPa modulates synap-tic plasticity in ways that strongly suggest a fundamental role for this APP-derived signaling protein in the regulation of learning and memory. We further showed that activation of the sAPPa signaling pathway can protect neurons against excitotoxic, oxidative and metabolic insults relevant to AD pathogenesis (Mattson et al. 1993). We also showed that the p-secretase-derived form of APP exhibits a marked decrease in physiological activity. The latter finding suggests that the shift in proteolytic processing towards increased p-secretase cleavage that may occur in AD may impair synaptic plasticity by decreasing levels of sAPPa.

Findings from our laboratory led to a new view of apoptotic biochemical cascades in the physiological regulation of synaptic plasticity and structural remodeling, and introduced the neuroscience field to the concept of "synaptic apoptosis." We showed that apoptotic cascades involving premitochondrial, mitochondrial and postmitochondrial components can be activated by physiological stimuli such as glutamate and trophic factor withdrawal in synaptic terminals and axons and dendrites. Moreover, the apop-totic cascades were shown to modify synaptic transmission and mediate structural remodeling of neuronal circuits, synapse loss and replacement. A specific example of our work in this area is the discovery that certain glutamate receptor subunits (AMPA receptor proteins GluR1 and GluR4) are direct substrates of caspase-3; cleavage of the subunits results in reduced AMPA currents and a resultant modification of synaptic function (Glazner et al. 2000). These findings reveal an entirely new function of apoptotic proteases as regulators of synaptic plasticity.

We have also contributed to the identification of the cellular and biochemical bases for the pathogenic actions of genetic mutations that cause early-onset inherited forms of AD. For example, we showed that presenilin-1 mutations cause synaptic dysfunction and increase the vulnerability of neurons to apoptosis and excitotoxicity by a mechanism involving an abnormality of calcium regulation in the endoplasmic reticulum (Guo et al. 1999). The calcium signaling defect was shown to involve overfilling of calcium pools. Presenilin-1 mutant knockin mice exhibited increased vulnerability to focal ischemic brain injury, suggesting a mechanism whereby presenilin mutations may promote neuronal degeneration under conditions of impaired energy metabolism (Mattson et al. 2000). Others had shown that presenilin-1 mutations and APP mutations result in increased production of Ap and decreased production of sAPPa. Our work revealed how this altered processing of APP causes a disruption of neuronal calcium homeostasis that may contribute to synaptic dysfunction and cell death in AD. These findings have identified novel therapeutic targets for drug development, including enzymes that process APP, and proteins that regulate neuronal calcium homeostasis.

While most work on presenilins and y-secretase have focused on APP as a substrate, we recentlyprovided evidence thaty-secretase-mediated cleavage of Notch renders neurons vulnerable to metabolic injury (Arumugam et al. 2006). Notch antisense transgenic mice, and normal mice treated with inhibitors of y-secretase, exhibit reduced brain cell damage and improved functional outcome in a focal ischemic stroke model. Notch endangers neurons by modulating pathways that increase their vulnerability to apoptosis and by activating microglial cells and stimulating the infiltration of pro-inflammatory leukocytes. These findings reveal Notch signaling as a novel therapeutic target for stroke and related neurodegenerative conditions. y-Secretase inhibitors have been developed for the treatment of AD but side effects associated with the long-term treatments required for this disease render them unlikely to be used in patients. In the case of stroke, on the other hand, short-term treatment with y-secretase inhibitors may prove effective in reducing brain damage without serious side effects. We also provided evidence that Notch signaling plays roles in synaptic plasticity in the adult brain (Wang et al. 2004). Mice with reduced Notch levels exhibit impaired LTP at hippocampal CA1 synapses. The Notch ligand Jagged enhances LTP in normal mice and corrects the defect in LTP in Notch antisense transgenic mice. Levels of basal and stimulation-induced NF-kB activity were significantly decreased in mice with reduced Notch levels. These findings suggest an important role for Notch signaling in a form of synaptic plasticity associated with learning and memory processes.

We have been working to identify dietary factors that may affect the risk of AD. We found that dietary restriction can increase the resistance of neurons in the brain to dysfunction and degeneration in animal models of relevance to the pathogenesis of Alzheimer's, Parkinson's and Huntington's diseases and stroke (Bruce-Keller et al. 1999; Duan et al. 2003; Maswood et al. 2004; Mattson 2005). The underlying mechanism was shown to involve increased production of neurotrophic factors, protein chaperones and mitochondrial uncoupling proteins, suggesting an hormesis response of brain cells to dietary restriction (Fig. 2). More recently, we have shown that dietary folic acid can protect neurons and improve behavioral outcome in an animal model of AD (Kruman et al. 2002). Folic acid deficiency results in elevated levels of homocysteine, resulting in an impaired ability of neurons to repair damaged DNA, which renders neurons vulnerable to being killed by Ap. The implication of these findings is that dietary

Molecular and cellular pathways towards and away from Alzheimer's disease

Dietary and Behavioral Neurohormesis

Dietary Restriction Physical Exercise 1

Cognitive Enrichment

Cellular Stress Response



Neuroprotection Neurogenesis Synaptic plasticity



Improved Glucose Metabolism

Resistan« to Neurodegenerative Disorders

Resistance to Diabetes and Cardiovascular Disease

Fig. 2. Three different environmental factors that may reduce the risk of AD (exercise, cognitive stimulation and dietary restriction) may activate similar adaptive cellular stress response pathways in neurons. (Modified from Mattson et al. 2004)

restriction and folic acid supplementation will decrease the risk of neurodegenerative disorders in humans. These findings provide an example of how basic research into the biochemistry and biology of neuronal plasticity and death have resulted in information that individuals can apply to their daily lives to reduce their risk of AD.


Jean François Dartigues

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