Targeting beta-amyloid pathology in Alzheimer's disease with Abeta immunotherapy

More than 10 clinical trials of Abeta immunotherapy are currently underway in patients with Alzheimer's disease (AD). The aim is to identify safe approaches for the efficacious antibody-mediated removal of brain beta-amyloid or its neurotoxic oligomeric precursors consisting of aggregated amyloid beta-peptide (Abeta). Initial experimental and neuro-pathological evidence for clearance of brain beta-amyloid in response to Abeta immunotherapy is associated with structural and functional rescue of neurons, as well as initial signs of clinical stabilization and reduced rates of dementia progression. For the next steps in the future improvement of Abeta immunotherapy, major challenges in pharmacokinetics, safety, and tolerability need to be addressed. These include the low penetrations rates of IgG molecules through the blood-brain barrier, possible reductions in brain volume, the possibility of autoimmune disease related to unwanted cross-reactivity with endogenous antigens on physiological structures, micro-hemorrhages related to cross-reaction with pre-existing vascular amyloid pathology, possible relocalization of Abeta from beta-amyloid plaques to brain blood vessels resulting in increased amyloid angiopathy, and the lacking activity of Abeta antibodies on pre-existing neurofibrillary tangle pathology, as well as the lacking molecular identification of the forms of Abeta to be therapeutically targeted. The solutions to these problems will be guided by the fine lines between tolerance and immunity against physiological and pathological structures, respectively, as well as by the understanding of the pathogenic transition of soluble Abeta into toxic oligomeric aggregation intermediates in the dynamic equilibrium of beta-amyloid fibril assembly. Provided that the ongoing and planned clinical trials address these issues in a timely manner, there is a good chance for Abeta immunotherapy to be one of the first disease-modifying therapies of Alzheimer's disease to be introduced into clinical practice

Hematopoietic CC-Chemokine Receptor 2 (CCR2) Competent Cells Are Protective for the Cognitive Impairments and Amyloid Pathology in a Transgenic Mouse Model of Alzheimer’s Disease

Monocytes emigrate from bone marrow, can infiltrate into brain, differentiate into microglia and clear amyloid β (Aβ) from the brain of mouse models of Alzheimer’s disease (AD). Here we show that these mechanisms specifically require CC-chemokine receptor 2 (CCR2) expression in bone marrow cells (BMCs). Disease progression was exacerbated in APPSwe/PS1 mice (transgenic mice expressing a chimeric amyloid precursor protein [APPSwe] and human presenilin 1 [PS1]) harboring CCR2-deficient BMCs. Indeed, transplantation of CCR2-deficient BMCs enhanced the mnesic deficit and increased the amount of soluble Aβ and expression of transforming growth factor (TGF)-β1 and TGF-β receptors. By contrast, transplantation of wild-type bone marrow stem cells restored memory capacities and diminished soluble Aβ accumulation in APPSwe/PS1 and APPSwe/PS1/CCR2−/− mice. Finally, gene therapy using a lentivirus-expressing CCR2 transgene in BMCs prevented cognitive decline in this mouse model of AD. Injection of CCR2 lentiviruses restored CCR2 expression and functions in monocytes. The presence of these cells in the brain of non-irradiated APPSwe/PS1/CCR2−/− mice supports the concept that they can be used as gene vehicles for AD. Decreased CCR2 expression in bone marrow–derived microglia may therefore play a major role in the etiology of this neurodegenerative disease