Stress-induced comorbidity of AD and PD
=> CRH, CRHR1, MAPT, KANSL1
NeuroMMSig CRH subgraph:
Stress up regulate CRH gene expression, which interacts with its receptor, the CRHR1 protein; the CRHR1 gene is highly expressed in hippocampus and the complex between the hormone and its receptor (CRH+CRHR1) can be detected in that brain region. In addition, the CRHR1 protein also interacts with γ-secretase, which is associated with Aβ accumulation, one of the hallmarks of AD pathophysiology. The hormone receptor protein complex (CRH+CRHR1) is further linked to the up-regulation of GSK3β and the phosphorylation of essential elements of the ERK1/2/MAPK pathway. Up-regulation of GSK3βis associated with MAPT hyper-phosphorylation; in addition, phosphorylated MAPT and ERK1/2/MAPK pathway up-regulate Neurofilament phosphorylation, which has been associated with AD. The complex physiology is even increased through the interaction of the ‘CRH+CRHR1’ protein complex with the BDNF protein; this interaction has already been associated with AD pathology. The complex also enhances neuronal activity by interacting with adenylate cyclase, cAMP, act(PAK), Ca2 signaling pathways. The resulting enhanced neuronal activity has been shown to further accumulateinterstitial fluid amyloid beta (ISF Aβ), while this accumulation of ISF Aβ is also linked with up-regulation of CRH gene expression,effectively establishing a feedback loop that can enhance negative dysregulation events.MAPT hyper-phosphorylation also increases its dissociation from microtubules, a process that has been linked to lewy-bodies and Parkinsonism, in the PD context. Finally, the CRHR1 antagonist ‘Antalarmin’, which is used in response of chronic stress, has been shown to reduceAβ accumulation in brain, adding further meaningful, supportive evidence in context.
Cartoon of the candidate mechanisms:
NeuroMMSig KANSL1 and endosomal lysosomal subgraphs:
KANSL1 is a subunit of two protein complex NSL1 and MLL1 that plays role in histone acetylation. This gene encode a nuclear protein that is involved in chromatin modification and belongs to histone acetyltransferase (HAT) complexes. In AD context, KANSL1 participate in histone acetylation inhibition and resulting in disruption of gene expression. KANSL1 also influences MAPT hyperphosphorylation thorough the MAPK pathway, MAPT is well-known biomarker for PD. The Amyloid-beta and oxidative stress inhibited CREB activity and further inhibits BDNF expression resulting in Long Term Potentiation which ultimately results in Hippocampal atrophy. the activated acetyled Tau inhibited the KIBRA normal function in actin polymerization which ultimately results in ong Term Potentiation dysfunction and Hippocampal atrophy. The CLU mutation which prevents the Micoroglia's phagocytosis, leads to the white matter degenaration through the dysregulation of Olygodendrocytes.
Cartoon of the candidate mechanism :