CNS & Neurological Disorders - Drug Targets

(Formerly Current Drug Targets - CNS & Neurological Disorders)

Stephen D. Skaper  
Department of Pharmaceutical and Pharmacological Sciences
University of Padova


Subcellular Injuries in Alzheimer's Disease

Author(s): Jean-Paul Tillement and Vassilios Papadopoulos

Affiliation: Research Institute of the McGill University Health Center, Montreal General Hospital, 1650 Cedar Avenue, C10-148, Montreal, Quebec H3G 1A4, Canada.

Keywords: Alzheimer's disease, β-amyloid, endoplasmic reticulum, Golgi, lysosomes, mitochondria, neurons, nucleus, plasma membrane.


Alzheimer’s disease (AD) is the most common form of dementia occurring in the elderly. Several hypotheses have been proposed to explain the pathophysiology of AD, including amyloidogenesis, disruption of calcium homeostasis, energetic failure, induction of oxidative stress, and hyperphosphorylation of tau protein. This review examines associations between cellular and subcellular injuries, neurodegeneration, and cell death in experimental models, clinical symptoms, and autopsy reports of AD to identify the subcellular events leading to disease onset and progression. The order in which these events occur is discussed. The first injuries reported in AD are subcellular and occur at the Golgi apparatus before any β-amyloid proteins deposit in the Golgi and endosomes. This is followed by lysosomal alterations and the inability of cells to clear β-amyloid. The next stage reveals functional changes and modifications in hippocampal synaptic transmission before structural changes are observed at the cellular level. Subsequently, an extensive intracellular inflammatory process develops in neurons and astrocytes. This inflammatory reaction begins in the nucleus, endoplasmic reticulum, endosomes and mitochondria, and is thought to lead to neurodegeneration and cell death. Finally, the neuroinflammatory response of chronically activated microglia escalates the neurodegeneration and cell death. Identifying the detailed sequence of subcellular events induced by the primum movens defect in AD may lead to the identification of novel drug targets for the treatment of the disease.

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

Page: [593 - 605]
Pages: 13
DOI: 10.2174/18715273113126660197