Molecular And Clinical Aspects Of Alzheimer’s Disease

The human brain is essentially a network of billions of nerve cells that communicate through specialized connections called synapses. Changes in the strength of these synapses, termed synaptic plasticity, are essential for learning and memory. Synaptic dysfunction leads to neurodegeneration observed in age-related disorders such as Alzheimer’s disease (AD). The disease presents itself with two distinguishing features in terms of its pathogenesis, one, the formation of neurofibrillary tangles, and the other, amyloid plaques. These plaques contain the -amyloid peptide (A), which either in the plaque-associated form or in its soluble oligomeric form is thought to set in a cascade of events that eventually leads to neurodegeneration. The reduction of amyloid, even in small measures, has been shown to alleviate the disease, and is the basis for much of the research attempting to understand and cure the disease. The neurotoxic A peptide is derived from a large type I transmembrane protein, the amyloid precursor protein (APP). APP is cleaved sequentially by two enzymes termed - and -secretase leading to the formation of the Aβ peptide. The key players in the processing of APP, i.e. -, -secretase and the substrate APP itself, are all membrane associated and hence are subjected to regulation by the lipid environment and membrane trafficking. Our work showed that these amyloidogenic cleavages occur in early endosomes followed by the routing of the cleaved product to late endosomes. Subsequently, A peptides can be released from the cells via the novel exosomal pathway. Exosomal proteins were found to accumulate in the plaques of AD patient brains suggesting a role in the pathogenesis of AD. Moreover, targeting a transient state analog, -secretase inhibitor to endosomes inhibited the secretase more efficiently than its soluble counterpart suggesting a novel therapeutic strategy. 
Lowering brain beta-amyloid is another major target for treatment or prevention of Alzheimer’s disease (AD). Current attempts to reduce brain beta-amyloid plaques include antibody-based immunization approaches. Passive antibody transfer protocols effectively removed amyloid plaques from brains of transgenic mice expressing AD-causing mutants in humans along with improvements in learning and memory. Initial clinical studies provided signs of clinical stabilization in subgroups of patients with AD as well as evidence for clearance of beta-amyloid from brain as demonstrated by PET imaging using PiB. To achieve the goal of successful clinical development of passive Abeta immunization major challenges have to be solved with regard to target and antibody optimization, pharmacokinetics, safety and tolerability. These include the low penetrations rates of IgG molecules through the blood brain barrier, the possibility of autoimmune disease related to unwanted cross-reactivity with endogenous antigens on physiological structures, microhemorrhages 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, the lacking activity of Abeta antibodies on pre-existing neurofibrillary tangle pathology, as well as the lacking molecular identification of the most toxic Abeta subtypes, e.g low molecular weight oligomers. 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.