Neuronal response in Alzheimer's and Parkinson's disease: the effect of toxic proteins on intracellular pathways

Abstract

Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deterioration and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen-activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and α-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed.

Fig. 1

Cellular trafficking of APP and Aβ. APP cleavage to peptides occurs both in lysosomes after its endocytosis and at the surface of cell membrane. The proteolysis products accumulate intracellularly or are released into extracellular space

Fig. 2

Aβ and GSK3. Aβ binding to membrane receptors such as insulin receptor (IR) inhibits the activity of Akt and wnt through PI3K inhibition. Inactivation of Akt and wnt consequently dephosphorylate GSK3 which causes tau hyper-phosphorylation and microtubular disorganisation

Fig. 3

Aβ and mitochondrial dysfunction. Attachment of Aβ to inner membrane of mitochondria alters the different aspects of mitochondrial activity. Blocking electron chain through reducing complex IV activity, damaging mitochondrial DNA (mtDNA), inhibiting tricarboxylic acid (TCA) cycle and ATP production, enhancing cytochrome c release and activation of apoptotic pathways, and increasing the mitochondria production of ROS are some of the examples

Fig. 4

α-Syn in normal condition binds to synaptic vesicle membrane and also v-SNARE. v-SNARE assembly to t-SNARE creates SNARE complex and results in synaptic vesicle fusion to cell membrane and neurotransmitter release. α-Syn clusters synaptic vesicles in the axonal terminal and produces a high concentration of presynaptic vesicles at a certain area of plasma membrane. Vesicular α-Syn also binds to early endosomes and facilitates neurotransmitter refilling of vesicles. α-Syn accumulation/fibrilation inhibits vesicular refilling, blocks SNARE complex formation and reduces the number of docking neurotransmitter vesicles