Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Abstract

Neurodegenerative diseases, exemplified by Alzheimer's disease and Huntington's disease, are characterized by progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Although there are differences in the exact sites of pathology, and the clinical profiles of these two conditions only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of exploiting common therapeutic targets for drug development. As Huntington's disease has a monogenic cause, it is possible to accurately identify individuals who carry the Huntington's disease mutation but do not yet manifest symptoms. These individuals could act as a model for Alzheimer's disease to test therapeutic interventions that target shared pathogenic pathways.

Figure 1. Therapeutic targets in synaptic dysfunction pathway

NMDAR receptor signalling can be triggered by glutamate released from the presynaptic neuron or through the NMDAR agonist quinolinic acid (QA), a product of tryptophan metabolic pathways in microglia. While glutamate signalling through synaptic NMDARs promotes neuronal survival, QA leads to excessive NMDAR activation and synaptic dysfunction. The levels of QA generation can be altered through inhibition of kynurenine 3-monooxygenase, an enzyme in the tryptophan metabolic pathway. An imbalance in synaptic and extrasynaptic NMDARs is seen in both HD and AD. Htt and Tau are both involved in regulating the trafficking of NR2B to the extrasynaptic membrane. NR2B-containing NMDARs are hyperphosphorylated as mHtt and Tau increase recruitment of kinases to NR2B-containing NMDARs. An increase in both the levels and phosphorylation of NR2B-containing NMDARs leads to an increased extrasynaptic NMDA current that triggers cell death through multiple pathways. Two major pathways leading to cell death in HD and AD are represented: 1) inhibition of CREB phosphorylation that inhibits pro-survival pathways and 2) increases in Ca2+ influx, leading to mitochondrial dysfunction. Therapeutic targets are highlighted in red; Drugs are highlighted in green.

Figure 2. Therapeutic targets in the neurotrophin pathway

BDNF and NGF levels are reduced in both HD and AD. Presynaptically, Htt, APP and Tau influence trafficking mechanisms via interaction with HAP1, kinesin and dynein/dynactin, influencing their binding to microtubules. Pro-BDNF and pro-NGF are processed by unknown proteases to generate mature BDNF and NGF. Furthermore, TrkA and TrkB receptor levels are decreased in AD and HD, respectively. Signalling through Trk receptors is reduced, thereby increasing Gsk3ß activity and enhancing cell death pathways. Increased p75NTR levels and signalling mediated by pro-BDNF and pro-NGF also triggers cell death. Therapeutics examined to date include: Epothilone D, BDNF, NGF, glucocorticoids and Lithium. Therapeutic targets are highlighted in red; Drugs are highlighted in green.

Figure 3. Therapeutic targets in the apoptotic pathway

The aberrant activation of caspase-6 that is seen in animal models and patients of both HD and AD could be mediated through multiple pathways: 1) Excitotoxicity, as described above, leads to an excessive influx of Ca²⁺, which can depolarize mitochondria and lead to caspase activation. 2) Aberrant signalling through trophic receptors or death receptors as outlined can result a release of cytochrome c and Smac/Diablo from mitochondria, which activate caspase-9 and inhibit Bcl-2 as well as IAP proteins. These events lead to a subsequent activation of caspase-6 by both blocking of inhibitory pathways as well as direct activation through caspase-9. 3) Caspase-6 and -3 could furthermore be activated through the intrinsic pathway, since evidence for DNA and mitochondrial damage, ER stress and protein misfolding as well as oxidative stress is found in AD and HD patients and animal models. Degradation of caspase-6 through the proteasome reduces its activity. Therapeutic targets are highlighted in red.

Figure 4. Therapeutic targets in the protein misfolding pathway

The disease proteins mHtt, Tau and Aβ undergo misfolding and aggregation, which is a multi-step process involving misfolded monomers, oligomers and large aggregate structures. Endogenous chaperone proteins of the Hsp family can inhibit aggregation and are likely able to interfere at different steps. Hsp’s can be transcriptionally upregulated through Heat shock factor 1 (Hsf-1), which in turn is activated by compounds such as Celastrol or Geldanamycin that are known to reduce protein aggregation and toxicity in cell culture and Drosophila models of AD and HD. Chemical compounds that directly interfere with the aggregation cascade are often identified as inhibitors of aggregate formation, and with the exception of EGCG it is unknown for most compounds at which step they interfere. Therapeutic targets are highlighted in red; Drugs are highlighted in green.

Figure 5. Therapeutic targets in the autophagy pathway

Upregulation of autophagy is an efficient way to clear disease proteins in AD and HD, and therapeutic interventions have been tested against a variety of different targets. The balance between inhibition of autophagy by Akt and activation by AMPK has been shifted through treatment with resveratrol analogs, which increase AMPK activity. Inhibition of GSK3β through Lithium prevents excessive Tau phosphorylation and allows pro-survival CREB signalling (see above), autophagy is increased through inhibition of the IMPase pathway. Inhibition of mTOR with rapamycin and analog compounds lifts the block on autophagosome formation and is beneficial in both AD and HD mouse models. An mTOR independent pathway activating autophagy can be triggered by treatment with Valproate and is mediated a decrease in Inositol and IP₃ levels. The Beclin 1-PI3K type III complex promotes autophagosome formation and loss or inhibition of either protein is detrimental in mouse and cell culture models of AD and HD. Autophagosomes not only engulf aggregates of disease proteins present in the cytoplasm but are also capable of generating Aβ through γ-secretase cleavage. Upon fusion with the lysosome, the autophagosome becomes acidic and lysosomal proteases such as the cathepsins degrade the disease proteins. Deletion of the endogenous cathepsin inhibitor cystatin B is beneficial in an AD mouse model. Furthermore mHtt interferes with lysosome function by impairing vesicle transport from the Golgi, resulting in a decrease of proteases in the lysosome. PSEN1 deletion or mutations interfere with the acidification of the lysosome, thus reducing the activity of lysosomal proteases and rendering autophagic protein degradation less efficient.