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Review
. 2019 Jul 19:14:5541-5554.
doi: 10.2147/IJN.S200490. eCollection 2019.

Alzheimer's disease: pathogenesis, diagnostics, and therapeutics

Sneham Tiwari  1 , Venkata Atluri  1 , Ajeet Kaushik  1 , Adriana Yndart  1 , Madhavan Nair  1
Affiliations
Review

Alzheimer's disease: pathogenesis, diagnostics, and therapeutics

Sneham Tiwari et al. Int J Nanomedicine. .

Abstract

Currently, 47 million people live with dementia globally, and it is estimated to increase more than threefold (~131 million) by 2050. Alzheimer's disease (AD) is one of the major causative factors to induce progressive dementia. AD is a neurodegenerative disease, and its pathogenesis has been attributed to extracellular aggregates of amyloid β (Aβ) plaques and intracellular neurofibrillary tangles made of hyperphosphorylated τ-protein in cortical and limbic areas of the human brain. It is characterized by memory loss and progressive neurocognitive dysfunction. The anomalous processing of APP by β-secretases and γ-secretases leads to production of Aβ40 and Aβ42 monomers, which further oligomerize and aggregate into senile plaques. The disease also intensifies through infectious agents like HIV. Additionally, during disease pathogenesis, the presence of high concentrations of Aβ peptides in central nervous system initiates microglial infiltration. Upon coming into vicinity of Aβ, microglia get activated, endocytose Aβ, and contribute toward their clearance via TREM2 surface receptors, simultaneously triggering innate immunoresponse against the aggregation. In addition to a detailed report on causative factors leading to AD, the present review also discusses the current state of the art in AD therapeutics and diagnostics, including labeling and imaging techniques employed as contrast agents for better visualization and sensing of the plaques. The review also points to an urgent need for nanotechnology as an efficient therapeutic strategy to increase the bioavailability of drugs in the central nervous system.

Keywords: amyloid beta; amyloid precursor proteins; amyloidogenesis; tau phosphorylation; β-secretases; γ-secretases.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Overview of fields of research that need to be elucidated to understand the pathophysiology of Alzheimer’s disease and develop therapeutic strategies against it.
Figure 2
Figure 2
An overview of the Aβ-pathogenesis hypothesis. Note: Amino-acid sequence of the Aβ fragment and location of action of α-, β-, and γ-secretases in diseased neurons within a diseased amyloidogenic pathway. Abbreviation: Aβ, amyloid β.
Figure 3
Figure 3
Alternative splicing of APP in amyloidogenic and nonamyloidogenic pathways. Note: Cleavage of APP by α- and γ-secretases in normal state and alternative cleavage by β- and γ- secretases in diseased state. Abbreviations: C83, 83-amino-acid carboxyterminal; C99, 99-amino-acid membrane-bound fraction; AICD, APP intracellular domain.
Figure 4
Figure 4
Hyperphosphorylationof τ. Note: Mechanism by which τ hyperphosphorylation leads to instability of the microtubule and finally microtubule subunits fall apart leading to formation of insoluble and big neurofibrillary tangles. Abbreviation: Aβ, amyloid β.
Figure 5
Figure 5
Mechanism of neuronal damage and Alzheimer's disease (AD) progression. Note: Extracellular and intracellular amyloid β and tangles cause extreme toxicity, resulting in synaptic damage and increased reactive oxidative stress that then leads to microglial infiltration around the plaque areas.
Figure 6
Figure 6
Semipermeable blood–brain barrier and transmigration route of the nanoparticles (NPs).
See this image and copyright information in PMC

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