What happens to the CNS in alzheimers disease (AL)?
loss of hippocampal and cortical neurons results in impaired memory formation and cognitive deficits
Alzheimers disease - main characteristics:
- progressive and irreversible loss of neurons from hippocampus and cortical areas
- genetic and environmental factors
- aggregation of Beta-amyloid plaques and intracytoplasmic neurofibrillary tangles
Aggregation of what proteins in alzheimers?
Beta-amyloid plaques and intracytoplasmic neurofibrillary tangles
Onset of alzheimers is when?
usually after age 65 in neurologically normal people
**Two types of AD symptoms:
- 1) cognitive
- loss of short term memory (poor recall and losing items)
- aphasia (difficulty remembering works to being completely unable to speak, read, or write)
- apraxia (cant carry out motor activities despite intact motor system)
- agnosia (inability to recognize objects, persons, sounds, shapes, or smells despite intact sensory system)
- disorientation (impaired perception of time; impaired executive function)
2) Non-cognitive: - depression
- psychotic symptoms (hallucinations/delusions)
- behavioral disturbances (aggression, motor hyperactivity, repetitive mannerisms, uncooperativeness)
Which AD symptoms appear initially?
cognitive symptoms
Main way to Dx AD?
Can also use?
- clinical assessment - need presence of dementia –> cognitive impairments beyond normal aging process
- also can use Neuroimaging - CT or MRI
initial manifestation of degenerative dementia is called? Relationship to AD?
- Mild cognitive impairment (MCI)
- some of these patients get AD and some dont
*death due to demensia how long?
6-12 years of AD onset
Gross pathology of AD?
massive tissue damage and decrease in brain volume
micro-pathology of AD?
1) neuronal degeneration and cortical atrophy
2) Neuritic plaques (amyloid or senile)
3) neurofibriallary tangles
Brain areas affected?
- hippocampus - memory
- frontal lobe - cognitive
- patietal and centers for language etc..
Cholinergic Hypothesis - how does it relate to alzheimers?
degeneration of subcortical cholinergic neurons = Deficiency of ACh ==> memory formation areas affected (hippocampus)
Early neuronal-finding of AD?
cholinergic deficit
severity of AD is directly correlated to…
loss of Ach activity
Amyloid hypothesis - how does it relate to alzheimers ?
- extracellular accumulations of Beta-amyloid peptides (betaA) that are toxic to neurons)
- deposition of betaA does not correlate well with neuronal loss
Where does Beta-amyloid come from?
betaA is cleaved from amyloid precursor protein (APP) on the cell membrane
**Early onset AD - amyloid hypothesis
- rare-
- related to mutations in:
- ->APP (amyloid beta precursor proteins) - more protein
- ->PSEN1 & PSEN2 (presenilin 1&2 membrane proteins involved in cleaving APP) = increased cleavage of APP
- ->mutations cause over production of betaA
**Late onset AD - amyloid hypothesis:
- common-
- ApoE enhanced proteolytic breakdown and clearance of betaA within and between cells
- mutation in ApoE=epsilon4 allele of APOE (apolipoprotein E) = not effective at degrading betaA
*Tau hypothesis - how does it related to AD?
- microtubule associated protein Tau
- tau provides support to microtubules and neuronal cytoskeleton
- -hyperphosphorylation of tau = forms aggregates and neurofibrillary tangles
- -microtubular disintegration and instability
- -collapse of neuronal transport system
- -altered NT release and synaptic function
- -cell death
***Two main cholinesterase enzymes that are blocked?
- acetylcholinesterase
- butyrylcholinesterase
Cholinesterase inhibitors MOA?
-reduce breakdown of endoenously released ACH, resulting in greater activation of postsynaptic Ach receptors
==>reduced phosphorylation of Tau
==>secretion of soluble APP returned toward normal
==>reduced betaA production
==>glutaminergic neurotransmission returns toward normal
Cholinesterase inhibitors for AD - list drugs?
Donepezil
Rivastigmine
Galantamine
NMDA (Glutamate) receptor inhibitors - list drugs:
Memantine
