Aging and Alzheimers

Question 1

Normal

Aged Brain

Answer 1

Normal aged brains:

• may have widened sulci and thinner gray layers, most don’t
  
  • consistently seen with neurodegenerative disorders
• neuron counts show small if any changes

Question 2

Normal Cognitive Decline

Causes

Answer 2

1. Loss of myelin
2. Decreases in neurotransmitters
3. Decreases in receptors

Question 3

Mild Cognitive Impairment

(MCI)

Answer 3

• Forgetful
• Poor decision making
• Deficit in judging time or sequence of steps
• Poor visual perception

Question 4

Alzheimer’s

Gross Brain

Answer 4

Typically see a great variation.

Changes associated with AD most profound in frontal and temporal lobes.

Question 5

Biological Junk

Answer 5

Accumulation of cellular debris or atypical biological/biochemical elements.

See with normal aging and age-related diseases.

• due to cell death or abnormal protein processing
• rich in cytoskeleton proteins
• can occur without symptoms
• Examples:
  
  • Lewy bodies
  • Pick bodies
  • granulovascular degeneration
  • Hirano bodies
  • Lipofuchsin
  • neurofibrillary tanges
  • senile plaques

Question 6

Lewy Body

Answer 6

Concentrated cytoskeletal proteins with halo.

Associated with Lewy Body Disease

Question 7

Pick Bodies

Answer 7

Condensed neurofilaments, tubules.

Accumulates within cells of hippocampus layer CA1.

Associated with Pick’s disease.

Question 8

Lipofuschin

Answer 8

Found in all aging cells.

Occupy a larger area of neuronal cytoplasm in the with normal aging.

Accumulates faster in neurodegenerative disorders.

Question 9

Cholingergic Hypothesis

Answer 9

Cognitive defects in AD due to loss of cholinergic neurons, esp. at basal forebrain.

Staining for choline acetyltransferase and acetylcholinesterase in N. basalis, n. accumbens, and ventral striatum consistent with theory.

Question 10

Genetic Factors

Answer 10

• Down’s syndrome
  
  • always gets Alzheimer’s disease
  • onset at age 30-40
  • have extra APP gene causing extra amyloid production
• Familial AD
  
  • have mutations in APP or presenillin genes
  • onset at 50-60

Question 11

Plaques and Tangles

Answer 11

Alzheimer’s disease characterized by amyloid plaques and neurofibrillary tangles.

• APP cleavage by 𝛽 or 𝛾-secretases produces A𝛽1-42 fragment
  
  • Presenillin mutations allow 𝛾-secretase access to cleavage sites → more toxic products
• Released from cells and forms plaques → toxic to neurons
• Hyperphosphorylation of Tau → forms tangles
  
  • intereferes with function
  • eventually kills cell releasing tangles
• Tau tangles and amyloid plaques combine to form neuritic plaques
  
  • ApoE4 gene promotes formation
• Abnormal depositis highly immunogenic causing inflammatory reaction which activates microglia
• Causes an amyloid cascade of inflammation and cell death

Question 12

Vascular Amyloid Hypothesis

Answer 12

• Endothelial call damage causes accumulation of activated platelets
• Patients with AD have abnormally activated platelets
• Platelets with high content of APP → contributes to amyloid load → inflammation
• A𝛽1-42 deposits seen around blood vessels
• Amyloid can enter brain via RAGE receptor
• Causes inflammation → cell death

Question 13

Prevention

Answer 13

• Chronic low dose Aspirin use showed decreased incidence of AD
• Mental activity show to lower AD risk

Question 14

AD

Current Treatments

Answer 14

1. AChE inhibitors
   
   • showed progression for some by 6-12 months
2. NMDA receptor antagonist
   
   • inhibits cell death in vivo
   • reduces excitotoxic glutamate effects in vitro

Question 15

Developing

Treatments

Answer 15

• Phospholipase inhibitors
  
  • inhibits neuron death and microglia response
  • stimulates HSP70 disaggregase functions
• Protease inhibitors
  
  • inhibit 𝛽 and 𝛾 secretases
  • slow production of toxic fragments