Molecular Pathogenesis and Interventional Strategies for Alzheimer's Disease: Promises and Pitfalls

Abstract

Alzheimer's disease (AD) is a debilitating disorder characterized by age-related dementia, which has no effective treatment to date. β-Amyloid depositions and hyperphosphorylated tau proteins are the main pathological hallmarks, along with oxidative stress, N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity, and low levels of acetylcholine. Current pharmacotherapy for AD only provides symptomatic relief and limited improvement in cognitive functions. Many molecules have been explored that show promising outcomes in AD therapy and can regulate cellular survival through different pathways. To have a vivid approach to strategize the treatment regimen, AD physiopathology should be better explained considering diverse etiological factors in conjunction with biochemical disturbances. This Review attempts to discuss different disease modification approaches and address the novel therapeutic targets of AD that might pave the way for new drug discovery using the well-defined targets for therapy of the disease.

Figure 1

Pathophysiology of Alzheimer’s disease. (1) Formation of beta-amyloid (Aβ) peptides through BACE. Under physiological conditions, APP is acted upon by the enzyme α-secretase to produce sAPPα fragments, which remain in the extracellular space, and carboxy-terminal 83-amino-acid (C83) fragments, which anchor in the plasma membrane. During a neuropathological situation, APP is first preferentially cleaved by BACE, which breaks down APP into sAPPβ in the extracellular space and a 99-amino-acid membrane-bound fraction (C99). Further processing of the C99 fragment by γ-secretase results in the formation of either Aβ(1–40) or Aβ(1–42) peptides, which are thought to be responsible for senile plaque formation. (2) Tau hyperphosphorylation resulting in neurofibrillary tangle formation, loss of synapse, cerebrovascular damage, and MG-AS activation due to Aβ oligomers. (3) NMDA excitotoxicity is caused by Mg²⁺ blockade of NMDAR, leading to calcium influx and neuronal death. (4) Cholinergic neuronal loss and cognitive dysfunction. Abbreviations: APP, amyloid precursor protein; sAPP-α, soluble fragment formed from APP after cleavage by α-secreatase; sAPP-β, soluble fragment formed from APP after cleavage by β-secreatase; BACE, β-secretase 1; C83, carboxy-terminal 83-amino-acid fragment; C99, carboxy-terminal 99-amino-acid fragment; MG, microglia; AS, astrocytes; NMDAR, N-methyl-d-aspartate receptor.

Figure 2

ApoE lipoprotein and Aβ metabolism in the brain. Aβ clearance is brought about by receptor-mediated uptake by glia and neurons, drainage into interstitial fluid, or through the BBB, and also by proteolytic degradation by IDE and neprilysin. Astrocytes and microglia synthesize Apo-E, which is lipidated by the ABCA1 transporter to form lipoprotein particles. This apolipoprotein binds to soluble Aβ and facilitates Aβ uptake through cell-surface receptors like LRP1, LDLR, and HSPG. Apo-E enhances binding and internalization of soluble Aβ by glial cells, disrupts Aβ clearance at the BBB, and influences CAA pathogenesis. Abbreviations: Aβ, beta-amyloid; ABCA1, ATP-binding cassette A1; Apo-E, apolipoprotein E; BBB, blood–brain barrier; CAA, cerebral amyloid angiopathy; HSPG, heparan sulfate proteoglycan; IDE, insulin-degrading enzyme; LDLR, low-density lipoprotein receptor; LRP1, low-density lipoprotein receptor-related protein 1; LXR, liver X receptor. Adapted from Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com/).

Figure 3

Interactions of RanBP9 with APP, LRP, and BACE1. RanBP9 promotes the endocytosis of APP and considerably increases its BACE1 cleavage to generate Aβ fragments. RanBP9 exerts pro-apoptotic activity by regulating B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax) protein levels in mitochondria. RanBP9 and p73 together induce abnormal changes in mitochondria (MMP, superoxide levels, apoptotic proteins, and fission) and bring about apoptosis.