Pathophysiology

Anatomical Pathology

Alzheimer’s disease affects multiple parts of the brain, including the temporal lobe, parietal lobe, frontal cortex, and cingulate gyrus. Alzheimer’s is characterized by neuron loss, which is responsible for the loss of memory, language, perception, and cognitive skills associated with the disease. According to Cummings et al. the histopathology of Alzheimer's disease includes neuritic plaques, neurofibrillary tangles, loss of synapses and neurons, granulovacuolar degeneration, AMY plaques, and amyloid angiopathy.5 All these causes lead to neuron death, which in turn leads to overall shrinkage of the brain.   

Brain comparison
Figure 1: Comparison of normal brain (left) with Alzheimer's brain (right)
http://www.labspaces.net/103390/Alzheimer_s_memory_problems_originate_with_protein_clumps_floating_in_the_brain

Amyloid Beta (Aβ)


Amyloid Beta is a derivative of the Amyloid Precursor Protein (APP), which is a protein that is believed to modulate neuronal excitability, synaptic plasticity, synaptogenesis, and neurite outgrowth.4 Amyloid Beta (
Aβ) is formed through cleavage of the APP, generating a peptide 36-43 amino acids long. The cleavage is performed by α, β, and γ secretases in the brain. Recent evidence suggests that oligomers of Aβ attach to receptor sites on dendrites that receive messages, which causes the neurons to lose function and die.3 In patients with Alzheimer’s disease, the Aβ oligomers also aggregate to form plaques. These plaques stimulate the production of free radicals which also leads to neuronal death.6 In addition, the plaques disrupt synapse networks by interfering with the dendrite path and reducing the number of spines that come out of the dendrites, which are essential to their signal transmission capabilities.3 Eventually, the degenerate neurons become clumped into the amyloid plaques which are insoluble and unable to be broken down by the body.  The accumulation of plaques in the brain causes loss of function and the symptoms of dementia characteristic of the diesase. 

Neuron comparison
Figure 2: Comparison of healthy neuron and Alzheimer's neuron
http://userwww.sfsu.edu/~art511_h/511final/alzheimerproposal/plaques.html

Neurofibrillary Tangles

The other main neuropathologic hallmarks of Alzheimer’s disease are the neurofibrillary tangles of tau protein.  Normally, tau proteins serve to stabilize microtubules in the neurons in the brain, and are essential for axonal growth and development.1 In the disease state, the tau protein becomes hyperphosphorylated, which disrupts their bonds to the microtubules and causes the microtubule structure to collapse. The dissociated tau protein becomes tangled and deposits inside the cell. The microtubules, which are like tracks for nutrients and other molecules to enter and leave the cell, become unable to retain their shape. The unstable microtubules disintegrate, which leads to apoptosis of the neuron.7 In Alzheimer's disease, the neurofibrillary tangles are concentrated in vulnerable, important neural systems, which causes severe loss of brain function. 

Plaques and Tangles
Figure 3: Image of amyloid plaques and neurofibrillary tangles in the brain
http://ladulab.anat.uic.edu/

Presenilin Mutations

Alzheimer’s disease is not normally a hereditary disease, although cases linked to genetics share a common problem: a mutation in the genes that code for the presinilin proteins.8 Presenilins are a set of proteins that are part of the gamma secretase complex, which helps cleave APP to form Aβ. Mutations in the genes PSEN1 and PSEN2 which code for the presenilins cause a higher rate of cleavage of the APP and cause a higher portion of the cleaved product to be of the more harmful Aβ type. 

References

  1. "Alzheimer's Disease." Cleveland Clinic Continuing Medical Education (CME). Web. 19 Nov. 2011. <http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/alzheimers-disease/>.
  2. "Beta-amyloid and Its Damaging Effects on Neurons." National Institute on Aging. Web. 19 Nov. 2011. <http://www.nia.nih.gov/alzheimers/publications/adprogress2005_2006/part2/beta_amyloid.htm.htm>.
  3. "Cellular Actions of Beta-amyloid Precursor Protein and Its Soluble and Fibrillogenic Derivatives." Physiological Reviews. Web. 19 Nov. 2011. <http://physrev.physiology.org/content/77/4/1081.short>.
  4. "Cellular Actions of Beta-amyloid Precursor Protein and Its Soluble and Fibrillogenic Derivatives." Physiological Reviews. Web. 19 Nov. 2011. <http://physrev.physiology.org/content/77/4/1081.short>.
  5. Cummings, Jeffrey L. "Alzheimer's Disease: Etiologies, Pathophysiology, Cognitive Reserve, and Treatment Opportunities." Neurology 51.1 (1998). MD Consult. Web. 19 Nov. 2011.
  6. Memory Loss & the Brain. Web. 19 Nov. 2011. <http://www.memorylossonline.com/glossary/amyloidplaques.html>.
  7. "Signaling Pathways: Amyloid Plaque and Neurofibrillary Tangle Formation in Alzheimer's Disease." Cell Signaling Technology. Web. 19 Nov. 2011. <http://www.cellsignal.com/reference/pathway/alzheimers_disease.html>.
  8. Web. 19 Nov. 2011. <http://www.ncbi.nlm.nih.gov/pubmed/9930863>.