How Can Insulin Resistance Cause Alzheimer's Disease?

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive decline. Despite worldwide efforts to find a cure, no proper treatment has been developed yet, and the only effective countermeasure is to prevent the disease progression by early diagnosis. The reason why new drug candidates fail to show therapeutic effects in clinical studies may be due to misunderstanding the cause of AD. Regarding the cause of AD, the most widely known is the amyloid cascade hypothesis, in which the deposition of amyloid beta and hyperphosphorylated tau is the cause. However, many new hypotheses were suggested. Among them, based on preclinical and clinical evidence supporting a connection between AD and diabetes, insulin resistance has been pointed out as an important factor in the development of AD. Therefore, by reviewing the pathophysiological background of brain metabolic insufficiency and insulin insufficiency leading to AD pathology, we will discuss how can insulin resistance cause AD.

Keywords: amyloid beta; dementia; hypometabolism.

Figure 1

Domains and secretase sites of action of the APP (Amyloid precursor protein). APP is a transmembrane protein composed of 6 domains. From the N-terminal region these domains include a cystein domain, an acidic domain, kunitz-type protease inhibitor domain (not present in APP₆₉₅), a glcosylated domain and a cytoplasmic domain. The glycosylated domain contains the amyloid beta sequence cleaved by α-, β-, and γ-secretase.

Figure 2

Non-Amyloidogenic and Amyloidogenic pathways of APP. In the non-amyloidogenic pathway, α-secretase cleavage of the Aβ region produces sAPPα and C83 fragments, and then γ-secretase cleavage of C83 produces p3 and AICD fragments which precludes Aβ formation. In the amyloidogenic pathway, cleavage of the Aβ region produces sAPPβ and C99 fragments. Then, the C99 fragment is cleaved by the γ-secretase complex into Aβ and AICD fragments. Accumulation of Aβs in the tissue forms plaque.

Figure 3

Aggregation of Aβ monomers to higher order oligomers, protofibrils and mature fibrils. Aβ monomers can form assemblies ranging from low molecular weight oligomers (dimers to pentamers) to mid-range molecular weight oligomers (hexamers to dodecamers). These oligomers can further aggregate into protofibrils and fibrils.

Figure 4

BBB transport of Aβ. Aβ is produced in the CNS, where it can aggregate into insoluble aggregates. Soluble Aβ can be transported across the BBB from brain to blook vis LRP. Aβ is also produced in peripheral tissues and can be transported from blood to brain via RAGE. LRP: low density lipoprotein receptor-related protein 1; RAGE: advanced glycation end product receptor.

Figure 5

Glucose and lactate delivery to nerve cells. Glucose is transported from capillaries to astrocytes via GLUT1. After entering the astrocyte, glucose is metabolized to lactate, then lactate is transported out into the interstitium via MCT1 and MCT4. Lactate enters into presynaptic and postsynaptic neurons via MCT2 and is used for energy metabolism after being converted into pyruvate. Glucose can also enter neurons directly via GLUT3. Blood capillary lactate enters into astrocytes via MCT1 and into neurons via MCT2. GLUT: glucose transporters; MCT: monocarboxylate transporter.

Figure 6

Insulin synthesis and insulin receptor. (A) Insulin biosynthesis begins as a precursor, preproinsulin, within the pancreatic β cell cytosol. Preproinsulin is comprised N-terminal signal sequence (gray), B-chain (orange), C-peptide (blue), and A-chain (yellow). Preproinsulin translocates into the endoplasmic reticulum and by cleavage of the signal sequence, forms proinsulin. The proinsulin folds by forming 3 disulfide bonds then trafficking through Golgi complex into secretory granules. Prohormone convertase and carboxypeptidase E processes proinsulin to C-peptide and mature insulin composed with A- and B-chain. ER: endoplasmic reticulum. (B) Insulin receptor is a dimer of identical units that span the cell membrane. Each of the 2 subunits is made of α-chain and β-chain, connected by a single disulfide bond. The α-chain is located extracellular and binds with insulin. The β-chain spans the cell membrane and has a tyrosine kinase domain which is activated when insulin binds to the α-chain.