VL21 Locus coeruleus

• 5% volume loss per decade after 40

• sharper decline after 70

• neurons

  • scale of gain not comparable to neuron loss during aging

  • new neurons debatable if they are as efficient als old neurons due to being integrated into already functioning system

• inflammation -> mostly chronic -> starts in locus coeruleus

• aggregation of

  • ß-amyloid plaques

  • neurofibrillary tangles (aggregated tau)

• normal aging but increased in alzheimers

• protein that lets you concentrate on mental activity ?

• Locus Coeruleus-norepinephrine System

• small nucleus in in PONS

• late-life cognitive abilities

• secretion of norepinephrine

• cognitive functions

• modulation episodic memory

• working memory

• inhibition irrelevant information

• main neuromodulator in brain

• novelty

• interest

• excitement

• arousal

• effort

  —> during all everyday tasks

  —> during perception of ongoing experience etc

• LCNE: support of activities assumed to protect against

  • cognitive impairment

  • cognitive decline

• support maintenance of effective cognitive function

  • keeping interested in environment, social engagement

—> Cognitive reserve effects

• LC-NE dysregulated

• removal of ß-amyloid impaired

• spreading neuropathology

BUT: - localized NE Release postulated to act against amyloid-induced toxicity

• LC neural density —> higher verbal knowledge

• decreased LC neural density associated with midl cognitive impairment & ALzheimers

• LC activity associated with better memory performance in older adults

• Alzheimers

  • less LC density -> less NE -> more neurofibrillary tangles

• often activated -> high metabolic demands -> high oxidant stress -> lot of waste

• plays a role in blood-brain barrier -> exposed to capillaries & toxins in these capillaries

• proximity to fourth ventricle -> contact with cerebrospinal fluid toxins

• 20-40% loss in neuron counts in LC-NE with age

• earliest site for neurofibrillary tangles -> leads to ß-amyloid plaques

• neurofibrillary tangles spread thorugh cortex

Increased NE leads to opposite effects

1. wakefulness -> increased ß-amyloid-peptide release -> prevention of their clearance

2. complexity of enriched environment -> protects against amyloid-induced toxicity & enhances long-term potentiation via

   1. nmda pathways

• average brain levels of NE have negative effects -> average level should not be too high —> accumulation of ß-amyloid

• transient phasic spikes in LC activity under arousal: protection agains amyloid induced toxicity

• Glutamate amplifies norepinephrinergic effects

• LC neurons conntected to many different areas in the brain

• LC neurons release NE through long axons

• norepinephrine amplifies signals when information is important vs. unimportant

• told what information is important (face / place)

• electric shock -> increased arousal

• LC -> NE release

• higher salient face releases glutamate

• higher glutamata -> local NE release in face area

• feedback loop —> clearer pattern in face are through hotspot

• place: less glutamate -> no loop -> more suppression

• NE -> highly active neurons become more excited

• less active neurons are suppressed

  —> norepinephrine amplifies signals when information is important vs. unimportant (goal-relevant)

  —> lot of glutamate in synaptic space —> releases NE —> NE docks onto ß-receptors and more glutamate is released

• supplying NE -> can improve cognition

• stimulating environments activate LCNE pathway -> enhance cognitino

• long-term cardiovascular training -> increased NE levels

• could be the mechanism through which education, intelligence and mental stimulation lead to cognitive reserve

maintenance of cognitive function despite advancing age