CNS & Neurological Disorders -Drug Targets

ISSN: 1871-5273

CNS & Neurological Disorders - Drug Targets
Volume 8, Number 1, March 2009

Contents

Active and Passive Aβ-Immunotherapy: Preclinical and Clinical Studies and Future Directions: Part I
Guest Editors: Michael G. Agadjanyan and David H. Cribbs


Editorial Pp. 1-6


The Role of Microglia in Antibody-Mediated Clearance of Amyloid-Beta from the Brain Pp. 7-15
D. Morgan
[Abstract] [Full Text Article] [PMID: 19275633 PubMed - indexed for MEDLINE]


Clearance of Amyloid-β Peptide Across the Blood-Brain Barrier: Implication for Therapies in Alzheimer’s Disease Pp. 16-30
R. Deane, R.D. Bell, A. Sagare and B.V. Zlokovic
[Abstract] [Full Text Article] [PMID: 19275634 PubMed - indexed for MEDLINE]


Quantitative and Mechanistic Studies of Aβ Immunotherapy Pp. 31-49
T.E. Golde, P. Das and Y. Levites
[Abstract] [Full Text Article] [PMID: 19275635 PubMed - indexed for MEDLINE]


Immunotherapy, Vascular Pathology, and Microhemorrhages in Transgenic Mice Pp. 50-64
D.M. Wilcock and C.A. Colton
[Abstract] [Full Text Article] [PMID: 19275636 PubMed - indexed for MEDLINE]


Targeting Generation of Antibodies Specific to Conformational Epitopes of Amyloid β-Derived Neurotoxins Pp. 65-81
M.P. Lambert, P.T. Velasco, K.L. Viola and W.L. Klein
[Abstract] [Full Text Article] [PMID: 19275637 PubMed - indexed for MEDLINE]




Abstracts


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Editorial:


[Back to top] [PMID: 19275633 PubMed - indexed for MEDLINE]
The Role of Microglia in Antibody-Mediated Clearance of Amyloid-Beta from the Brain
D. Morgan

[Full Text Article]

Immunotherapy has emerged as a leading new approach to the reduction of amyloid deposits in the brains of Alzheimer patients. At least 4 distinct actions of anti-Aß antibodies have been proposed as contributing to the inhibition of amyloid deposition and its clearance. Critically, each of these proposed mechanisms may be acting simultaneously, and it is feasible that different antibodies may utilize each mechanism to a different extent. One of these proposed mechanisms involves the activation of microglia and the phagocytosis of Aß peptide. In general this is assumed to proceed through the Fcγ-receptor binding by antibody opsonized Aß aggregates, however modifying the microglial phenotype into one with a greater propensity for phagocytosing Aß is also feasible, as microglia avidly phagocytose Aß in vitro without antibody present. Evidence is presented supporting arguments that microglial activation does play a role in amyloid removal, particularly compacted amyloid deposits, under certain conditions. In addition to the specific antibody used, other considerations in comparing different reports of antibody action in APP mice include the age of the mice, the extent of pre-existing amyloid when therapy is initiated, the time point when the effects of the therapy are examined and the route of antibody administration. Future questions will consider the source of the activated microglia near the plaques after antibody administration (resident or peripheral) and the extent to which shifts in the microglial phenotype mediate some of the amyloid lowering actions of immunotherapy.


[Back to top] [PMID: 19275634 PubMed - indexed for MEDLINE]
Clearance of Amyloid-β Peptide Across the Blood-Brain Barrier: Implication for Therapies in Alzheimer’s Disease
R. Deane, R.D. Bell, A. Sagare and B.V. Zlokovic

[Full Text Article]

The main receptors for amyloid-beta peptide (Aβ) transport across the blood-brain barrier (BBB) from brain to blood and blood to brain are low-density lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE), respectively. In normal human plasma a soluble form of LRP1 (sLRP1) is a major endogenous brain Aβ ‘sinker’ that sequesters some 70 to 90 % of plasma Aβ peptides. In Alzheimer’s disease (AD), the levels of sLRP1 and its capacity to bind Aβ are reduced which increases free Aβ fraction in plasma. This in turn may increase brain Aβ burden through decreased Aβ efflux and/or increased Aβ influx across the BBB. In Aβ immunotherapy, anti-Aβ antibody sequestration of plasma Aβ enhances the peripheral Aβ ‘sink action’. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Aβ antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Aβ anti-body/Aβ immune complexes are rapidly cleared from brain to blood via FcRn (neonatal Fc receptor) across the BBB. In a mouse model of AD, restoring plasma sLRP1 with recombinant LRP-IV cluster reduces brain Aβ burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Aβ is required for its direct interaction with sLRP and LRP-IV cluster which is completely blocked by the receptor-associated protein (RAP) that does not directly bind Aβ. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Aβ ‘sink’ action, hold potential to reduce brain Aβ and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.


[Back to top] [PMID: 19275635 PubMed - indexed for MEDLINE]
Quantitative and Mechanistic Studies of Aβ Immunotherapy
T.E. Golde, P. Das and Y. Levites

[Full Text Article]

There is substantial and compelling evidence that aggregation and accumulation of amyloid β protein (Aβ) plays a pivotal role in the development of Alzheimer’s disease (AD); thus, numerous strategies to prevent Aβ aggregation and accumulation or to facilitate removal of preexisting deposits of Aβ are being evaluated as ways to treat or prevent AD [1, 2]. Pre-clinical studies in mice demonstrate the therapeutic potential of altering Aβ deposition by inducing a humoral immune response to fibrillar Aβ42 (fAβ42) or passively administering anti-Aβ antibodies (Abs) [3, 4], and both passive and active anti-Aβ immunotherapeutic approaches are now being tested in humans. Although a variety of mechanisms have been postulated regarding how Aβ immunotherapy might work to attenuate or in some circumstances clear Aβ from the brain, no mechanism has been definitively proven or disproven. Herein, we will review the various mechanisms that have been postulated. In addition we will discuss how a more thorough understanding of the pharmacokinetics of anti-Aβ Abs and their effects on Aβ levels and turnover provides insight into both the therapeutic potential and limitation of Aβ immunotherapy. We will conclude with a discussion of additional experimentation required to better understand the mechanism of action of anti-Aβ Abs in AD and optimize antibody (Ab) mediated therapy for AD.


[Back to top] [PMID: 19275636 PubMed - indexed for MEDLINE]
Immunotherapy, Vascular Pathology, and Microhemorrhages in Transgenic Mice
D.M. Wilcock and C.A. Colton

[Full Text Article]

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder that results in severe cognitive decline. Amyloid plaques are a principal pathology found in AD and are composed of aggregated amyloid-beta (Aß) peptides. According to the amyloid hypothesis, Aß peptides initiate the other pathologies characteristic for AD including cognitive deficits. Immunotherapy against Aß is a potential therapeutic for the treatment of humans with AD. While anti-Aß immunotherapy has been shown to reduce amyloid burden in both mouse models and in humans, immunotherapy also exacerbates vascular pathologies. Cerebral amyloid angiopathy (CAA), that is, the accumulation of amyloid in the cerebrovasculature, is increased with immunotherapy in humans with AD and in mouse models of amyloid deposition. CAA persists in the brains of clinical trial patients that show removal of parenchymal amyloid. Mouse model studies also show that immunotherapy results in multiple small bleeds in the brain, termed microhemorrhages. The neurovascular unit is a term used to describe the cerebrovasculature and its associated cells-astrocytes, neurons, pericytes and microglia. CAA affects brain perfusion and there is now evidence that the neurovascular unit is affected in AD when CAA is present. Understanding the type of damage to the neurovascular unit caused by CAA in AD and the underlying cause of microhemorrhage after immunotherapy is essential to the success of therapeutic vaccines as a treatment for AD.


[Back to top] [PMID: 19275637 PubMed - indexed for MEDLINE]
Targeting Generation of Antibodies Specific to Conformational Epitopes of Amyloid β-Derived Neurotoxins
M.P. Lambert, P.T. Velasco, K.L. Viola and W.L. Klein

[Full Text Article]

Individuals with early Alzheimer’s disease (AD) suffer from a selective and profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by toxic Aβ oligomers (also known as ADDLs). ADDLs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. The AD-like cellular pathologies induced by ADDLs suggest their impact could provide a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Discovery of these new toxins has provided an appealing target for disease-modifying immunotherapy. For optimal protection against these toxins, antibodies should bind to the pathological oligomers without being depleted by their monomeric subunits, which are rapidly generated by membrane protein turnover. A solution to this problem is likely to come from the continued development of conformation-specific antibodies, as described here. Prototype conformation-specific antibodies, not yet in the clinic, have been introduced and utilized in multiple applications for their ability to bind with high specificity and affinity to ADDLs. It can be anticipated that further development of such antibodies for use in clinical trials will come in the near future.