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"Cure" for Alzheimer's disease

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Mission

The Matsuoka Laboratory’s goal is to develop therapeutic approaches and agents to treat or prevent neurodegenerative diseases, such as Alzheimer’s disease (AD).

His lab moved from Nathan Kline Institute / New York University Medical Center to Georgetown University in the fall of 2003. The new environment and AD collaborators at Georgetown University have added a clinical approach to the research activities.

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"Cure for Alzheimer's disease"--Development of therapeutic approaches and pharmacological agents for treatment of Alzheimer's disease

Alzheimer’s disease (AD) is a neurodegenerative affliction associated with memory dysfunction. Two classes of drugs are approved by FDA for treatment of AD, and they are effective at some degree. However, effect of currently available medications are only symptomatic and some patients do not tolerate for medications. Disease-modifying agents is desired for cure of AD. We aim to develop therapeutic approaches and pharmacological agents (drugs) based on multiple cascades; anti-amyloid beta (Abeta), anti-tau phosphorylation, and neuroprotection.

For quick review ----- Power Point slide show   Acrobat (contents are identical)

Brief background of Alzheimer's disease

Anti-amyloid beta (Abeta) approaches

Sequestration (also called "peripheral sink" approach)

Secretase modulators

Anti-tau phosphorylation approach

Neuroprotective agents

Development of optimal animal model to test neuroprotective agents

For further reading

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Brief background

Pathological hallmarks of Alzheimer’s disease (AD): Pathological hallmarks of Alzheimer’s disease (AD): AD is a neurodegenerative affliction associated with memory dysfunction (Selkoe, 2001). Senile plaques, neurofibrillary tangles, and significant neuronal cell loss are pathological hallmarks of AD (A-C, respectively, in the figure). Amyloid beta (Abeta) is the major component of senile plaques (A in the figure), and many proteins are co-deposited on and around the plaques. Hyper-phosphorylated tau (abnormal tau) is the major component of neurofibrillary tangles (panel B in the figure). Panel C is the postmortem whole brain; it is evident that the right brain has suffered significant atrophy. The right brain is from a case with AD, and the left is a non-demented control case.

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Currently available medications: Currently two classes of drug are approved by the FDA for the treatment of AD. Acetylcholinesterase (AChE) inhibitors were the first FDA-approved class of anti-AD drugs. Three of these drugs were approved between 1997 and 2001 and commonly prescribed: donepezil (Aricept®), rivastigmine (Exelon®) and galanthamine (Reminyl®) (Alzforum web site). Tacrine (Cognex®), the first cholinesterase inhibitor drug, was approved in 1993 but is rarely prescribed today because of associated side effects, including liver toxicity. Memantine (Namenda®), representing a new class of AD therapeutics, was approved in 2003 by the FDA for the treatment of moderate-to-severe AD. Memantine is a non-competitive low-to-moderate affinity NMDA receptor antagonist. While AChE inhibitors are symptomatic medications, NMDA receptor antagonists were thought to be neuroprotective,(i.e., disease-modifying). However, clinical evidence suggest that the benefits of memantine, like the cholinesterase inhibitors, are symptomatic. Currently available medications are effective but only show symptomatic efficacy (Reisberg et al., 2003), and some patients do not tolerate the medications. Effective disease-modifying agents are needed to slow the clinical progression of AD.

 

Our approaches: Our group currently focuses on anti-Abeta, anti-tau phosphorylation and neuroprotective approaches, because these can modify disease progression; i.e. cure for AD. Our study includes multiple components; understanding the mechanism of therapeutic approaches, development of optimal tools for in vivo and in vitro drug screening, identification of promising candidates in both vitro (test tube study) and vivo (pre-clinical study). We collaborate with clinical team and provide inputs to each other. See below for more details of each approach.


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Anti-amyloid beta (Abeta, also abbreviated as "Aβ") approaches

 

Abeta is generated from a larger precursor protein (APP) by enzymes (secretases) (Hardy and Selkoe, 2002). Generated Abeta is soluble and is cleared from the brain under healthy conditions, but uncleared Abeta start to form polymers. Highly pomymerized (called fibril Abeta because they look like fibril under electron microscopy) Abeta is deposited in the extracellular space. Traditionally, deposited Abeta is the toxic form, but recent evidence suggests that oligomers are the most toxic in relation to learning and memory aspects (Walsh and Selkoe, 2004). Therefore, “reduction of Abeta production through modulation of secretase activity" and “enhancement of Abeta metabolism and clearance” are possible therapeutic targets.

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Enhancement of Abeta clearance, ”Sequestration"
 

Anti-Abeta antibodies, evoked in response to active immunization with Abeta peptides, reduced brain Abeta burden in amyloid forming mice (vaccination approach) (Schenk et al., 1999). This vaccine-based clinical trial was suspended after severe brain inflammation in some patients (Birmingham and Frantz, 2002). The approach taken by the Matsuoka Lab does not rely on immune modulation. The Lab and collaborators found that plasma Abeta levels were significantly elevated during vaccine treatment (Lemere et al., 2003). Based on this evidence, it was hypothesized that alterations in CNS/peripheral Abeta equilibrium could reduce brain Abeta and, more importantly, that this could be achieved using drugs other than antibodies. The Lab tested two non-immune related proof-of-concept compounds in an Alzheimer’s disease mouse model and found reduction of brain Abeta load without the compounds entering the brain (Matsuoka et al., 2003) (see the figure for the hypothesized mechanism). We are investigating the mechanism of this therapeutic approach. The proof-of-concept drugs used in the previous study are not optimal for clinical use for various reasons; therefore, we are developing new drugs based on the sequestration hypothesis.

 

Recent Progress: We found that a modified antibody which no longer has immunemodulation but maintains affinity to Abeta, evoked Abeta sequestration (submitted for publication). The modified antibody may be useful for treatment of AD.


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Secretase modulators

Abeta is processed from the precursor, amyloid precursor protein (APP). Levels of Abeta can be modified by interrupting APP processing. There are various Abeta fragments and some fragments are less toxic than others. Abeta fragments composed of 1-40 and 1-42 amino acid residues are the most toxic form. Toxic Abeta fragments, Abeta 1-40 and 1-42, are generated by cleavage of N and C terminus by beta and gamma secretases, respectively (beta-secretase is also called "BACE"). Agents that inhibit these secretases are therefore a therapeutic target (Citron, 2002). Genetically manipulated mice lacking the BACE gene (called "knockout mice") confirmed that BACE inhibition is a potential approach. On the other hand, the absence of the gamma secretase gene proved to be lethal in mice during development. These evidences suggest that BACE is probably a better.We are developing BACE1 inhibitor through collaboration, and also investigate the mechanism of BACE1 inhibition.

Recent Progress: Transgenic mice overexpress mutant APP are commonly used to investigate secretase inhibitors. Sporadic AD who represent majority of AD patients, are free from mutation and APP expression is not upregulated. Non-transgenic mice have physiologically-relevant APP expression, but the optimal quantification system was not available. We developed full-length mouse Abeta ELISA, and investigated BACE1 inhibition mechanism using BACE1 knockout mice and a BACE1 inhibitor. We also found compensatory upregulation of other secretases in response to BACE1 inhibition (submitted for publication).

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Anti-tau phosphorylation approaches

 

Neurofibrillary tangles, which are composed by hyper phosphorylated tau, are another neuropathological hallmark of AD. It is believed that inhibition of hyperphosphorylation is beneficial. The enzyme which phosphorylates tau is known; thus the most simple approach is inhibition of the phosphorylation enzyme. Since tau pshophorylation is also physiological event, inhibition of phosphorylation enzyme may inhibit physiological functions. We are seeking approaches to prevent hyper (not physiological) phosphorylation tau.

 

Recent Progress: Tau and tubulin bind under physiologcal condition. We found a pharmacological agent which interfere tau/tubulin binding prevent tau hyper phosphorylation and cognitive impairment (under preparation for publication).


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Neuroprotective agents

 

Significant cell loss is seen not only in AD, but also in other CNS diseases such as Parkinson's. Neuroprotective agents that we are currently developing may work in other neurodegenerative diseases. We have two leading neuroprotective agents and are testing them in both in vivo and in vitro conditions. Many experimental neurodegeneration models, such as ischemia and glutamate injections, exhibit significant neurodegenerative damage and cell loss; however, these models do not recapitulate the neurodegeneration occurred in non-acute neurodegenerative diseases. Thus, we are also developing an optimal animal model, which is more relevant to AD-type neurodegeneration and is also a non-invasive biomarker to evaluate neuroprotective therapeutic approaches/agents.

 

Recent Progress: To develop pharmacological agents for neuroprotection, a model with AD-type neurodegeneration is essential. We are currently focusing to develop optimal animal models, see below.
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Development of optimal animal model to test neuroprotective agents

Enhanced neurodegeneration, including massive cell loss and brain atrophy, is one of the most critical features in AD. Also, humans exhibit a correlation between the rate of brain atrophy and changes in cognitive status, as well as between higher plasma homocysteine levels and increased hippocampal atrophy. However, none of the standard AD mouse models demonstrate neurodegeneration as such. To overcome these limitations, we manipulate plasma homocysteine levels through diet to induce neurodegeneration and brain atrophy. We use two techniques to quantify neurodegeneration; stereology-based histological assessments and non-invasive magnetic resonance imaging (MRI) (see below).

 

Recent Progress: We established method to quantify brain atrophy. Mouse brain is small (<1 inch), and minor movement during the scan affects. Thus, we developed new brain stereotaxic folder, which minimizes the brain movement. New folder significantly improved image quality. We induce hyper homocysteinemia, scan mice at multiple time points to investigate brain atrophy.

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For further reading

  • Alzforum web site is very useful site for further reading.

  • Birmingham K, Frantz S (2002) Set back to Alzheimer vaccine studies. Nat Med 8: 199-200. [PubMed link]

  • Citron M (2002) Beta-secretase as a target for the treatment of Alzheimer's disease. J Neurosci Res 70: 373-379. [PubMed link]

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297: 353-356. [PubMed link]

  • Hutton M, Perez-Tur J, Hardy J (1998) Genetics of Alzheimer's disease. Essays Biochem 33: 117-131. [PubMed link]

  • Lemere CA et al. (2003) Evidence for peripheral clearance of cerebral Abeta protein following chronic, active Abeta immunization in PSAPP mice. Neurobiol Dis 14: 10-18. [PubMed link]

  • Matsuoka Y et al. (2003) Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to beta-amyloid. J Neurosci 23: 29-33. [PubMed link]

  • Neve RL (2003) A new wrestler in the battle between alpha- and beta-secretases for cleavage of APP. Trends Neurosci 26: 461-463. [PubMed link]

  • Reisberg B et al. (2003) Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 348: 1333-1341. [PubMed link]

  • Schenk D et al. (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400: 173-177. [PubMed link]

  • Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81: 741-766. [PubMed link]

  • Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 44: 181-193. [PubMed link]

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