Protein misfolding and aggregation contribute to the pathophysiology of neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s diseases (PD). In physiological situations protein misfolding is sensed by the cellular control systems as a threat which is then followed by an immediate response. Any delay detecting the misfolded proteins, may result in damage and progression of neurodegenerative disorders [1, 2]. Unfortunately, not all the cellular responses to misfolded proteins are neuroprotective. Activation of some intracellular pathways as a part of this response occasionally create further damage, interruption in synaptic connections and neuronal apoptosis [3, 4].

Pathophysiology of toxic proteins

All the proteins implicated in neurodegenerative diseases share the common pattern of dysfunctional structure due to an unusual folding [5–7]. Through folding, proteins acquire the three dimensional structures required to undertake their biological functions. This process is prone to errors, causing the protein not to acheive its functional structure, building a toxic protein deposition. When an aggregation status is established, disaggregation rarely occurs because under physiological conditions, the equilibrium is in favour of aggregation [8–11]. These early aggregates are believed to be the source of toxicity in neurodegenerative disorders.

Alzheimer’s disease (AD)

AD is the most common form of dementia and among the leading causes of death in adults. AD is associated with two main lesions: extracellular plaques made of beta-amyloid (Aβ) and intracellular neurofibrillary tangles (NFT) made of tau protein [12, 13]. The plaques are the consequences of abnormal protein folding and aggregation with direct and indirect toxic effects on neuronal survival [14, 15].

Aβ biochemical structure and toxicity

Aβ, the principle protein implicated in development of AD, is derived from amyloid precursor protein (APP). More than ten isoforms of the protein are characterized by different lengths of amino acid chains, and among them APP695 is exclusively expressed in neurons. The transmembrane region of APP is placed near the c-terminus, and contains a Kunitz-type protease inhibitor (KPI) domain, which acts as a potent inhibitor of coagulation factors IXa and XIa, however, APP695 lacks the KPI domain [16, 17].

APP can act as a receptor for a signalling glycoprotein F-spondin that is released by neurons and possesses roles in axonal guidance, neuronal differentiation and neuro-repair [18, 19]. Some other functions of APP have also been proposed, including serving as a link between kinesin and synaptic vesicles being an adhesion protein, a role in metal ion homeostasis, neuroprotection and a function relating to promotion of neurite growth [16, 20].

APP is degraded in lysosomes [21–23] (Fig. 1). Aβ is produced when a normal cleavage of APP occurs α and β secretase cleave APP, outside the membrane. Also three members of a family of peptidase proteins, ADAM, (a disintegrin and metalloproteinase) have a recognized role cleaving the extracellular portion of APP, in the same way that α-secretase does [24]. Proteolysis of APP by β-secretase cleaves APP695 after Met-596 and produces a large soluble N-terminal (sAPPβ) and a small membrane-bound C-terminal fragment (C99), sAPPβ, is neuroprotective and regulates synaptic plasticity. This larger fragment of APP can also act as a microtubule associated protein (MAP) [25].

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 Full size image

APP can undergo proteolysis at the cell surface. Its C99 fragment can be processed by γ- secretase, presenilin 1 and 2, γ-secretase produces Aβ isoforms of 1-40, 1-42 or 1-43 [17, 26–28]. These peptides are made throughout life, but in AD they accumulate due to either increased production or decreased degradation or removal. Remaining Aβ has the potential to enhance its own production in cerebrovascular smooth muscles and hippocampal neurons [29, 30]. Excess peptides, particular those of Aβ 1-40, 1-42 and 1-43, form toxic aggregates, which result in progression of AD [16, 31, 32].

Filaments of amyloid structure are approximately 10 nm wide and 0.1–10 μm long with a β-sheet structure in their motif [33, 34]. Using Electron Paramagnetic Resonance Spectroscopy (EPRS) the β-sheet structure was obtained for both Aβ 1-40 and 1–42, two of the most toxic forms of amyloid protein [35, 36].

Aβ oligomers can be generated both extra- and intracellularly. Extracellular Aβ toxicity could be mediated through binding to receptors such as NMDA and disrupting the calcium balance of the neuron [37, 38]. Extracellular Aβ is internalized, stored in the lysosomes and can leak into the cytosol by destabilization of the lysosome membrane. Aβ oligomers have the ability to inhibit the function of proteasomes causing neuronal apoptosis [39, 40]. Toxicity of fibrillar and oligomers of Aβ also occurs through cytoskeletal disruption, tangle development, loss of synapses and inhibition of hippocampal long-term potentiation (LTP). This is the so-called “Aβ cascade theory” of AD [12, 41, 42].

Intracellular inclusions of Aβ have been found within neuronal compartments. [43, 44]. Internalization of Aβ occurs either via binding to low-density lipoprotein related protein-2 (LRP2) [45], LRP-1 [46, 47] or to a receptor for advanced glycation end-product (RAGE) [48]. The presence of Aβ in various subcellular compartments, suggests different sites for APP proteolysis, such as Aβ40 in the trans-Golgi network and Aβ42 in the endoplasmic reticulum (ER) [49, 50] as well as Golgi compartments [51]. Autophagic vacuoles enriched with presenilin-1 (PS1), APP and Aβ are found frequently in degenerating neurons in patients with AD. This suggests an essential role for autophagy in clearing the aggregated peptide through a lysosomal-dependent pathway [52].

Aβ disrupts APP trafficking, and initiates a pathological cascade of Aβ accumulation [39, 43]. An accumulation of vacuoles filled with Aβ occurs as a result of interruption to neuronal trafficking associated with the disruption of autopghgosomes [53]. Aβ itself is also able to activate the adenosine monophosphate kinase (AMPK) pathway, generating more autophagic vacuoles [54]. Thus, AD patients appear to produce abundant extracellular Aβ, resulting in plaque formation with a high level of toxicity causing extensive neuronal apoptosis [55–57].