Alzheimer's Disease (Dementias)
where do amyloid plaque first appear? where do they spread to as the disease progresses?
Amyloid plaques and neurofibrillary tangles begin in the hippocampus/ enterohinal - Then progresses to other brain regions, frontal and temporal lobes, affecting additional functions
what are amyloid plaques? what is their effect on the brain?
Amyloid plaques are aggregates of β-amyloid (αβ) peptide - Induces oxidative stress (free radical formation), disrupts neuronal membrane protein functions (inhibits Na/K+ pump) leads to excitotoxicity and neuronal cell death So amyloid plaques are neurotoxic
How are amyloid plaques produced in alzheimers disease?
Amyloid plaques are produced from the breakdown of AP, a membrane spanning protein 1) APP is normally cleaved first by is α-secretase or by β-secretase 2) Then cleaved again by gamma-secretase to generate β-amyloid (Aβ)
what is the role of APOE4 in alzheimers disease?
ApoE4 gene -> which codes for Apolipoprotien E - major risk factor - 3-12 fold depending in the polymorphism/isoform In the brain, Apolipoproteins are produced by astrocytes - Apolipoprotiens are normally transport cholesterol in the blood and helps cell internalize cholesterol and triglycerides - However ApoE4 also binds to amyloid β-proteins and is present in senile plaques and neurofibrillary tangles therefore it may facilitate the precipitation of amyloid (may have interactions with Aβ and presenilins)
what is Alzheimers disease characterized by/as?
Characterized by both progressive cognitive decline and neuropathology - Describe as memory loss progressing to wide range of other cognitive impairments, then emotional/ personality changes and finally dementia (general decline in intellectual function, disorientation, dependence on care-takers)
describe the symptoms of alzheimers disease (from early symptoms to end stage). relate this to the progresion of the disease pathology
Cognitive decline begins with memory impairment 1st -memory impairment for recent events, the loss of remote memories - Spatial thinking, navigation is impaired early, "how did I get home" -> the loss of synapse usually beings in the hippocampus and parahippocampa gyrus - hippocampus is necessary for memory formation - hippocampus is also necessary for spatial orientation and nagivation 2nd - "absent- mindedness": deficits in working memory and executive function "what was I about to do?" -> plaque formation in the temporal lobe would result in significant memory loss Late Stage dementia - Generalized impairment in cognition and behavioral regulation - remote retrograde amnesia, disorientation, gradual loss of independence -> as the disease progresses it moves to the frontal and temporal lobes Damage to the prefrontal cortex would result in - loss of executive function - behavioral changes
How is alzheimer's disease diagnosis confirmed?
Diagnosis still confirmed by post-mortem neuropathology examination - by the presence of amyloid plaques and neurofibrillary tangles New neuroimaging techniques in development to asses neuropathology
familia/genetic forms of alzheimers disease is usually due to ___? what causes?
Due to mutations of three genes, which are inherited dominantly - Presenilins (PS1 and PS2) - APP gene - ApoE4 All three of these mutations increase Aβ synthesis
what is the pathological processes of ahlzeimer's disease due to amyloid plaques and neurofibrillary fibers?
Loss of synapses which are most notable in the layers 2 and 3 of the cerebral cortex - These layers send out and receive association connections Pathological changes are more severe in Association* areas of the frontal* and temporal* lobe than in the primary sensory and motor area - Earliest changes occur regularly in the hippocampus and parahippocampus gyrus ( especially in enterohinal* cortex, input to dentate gyrus) -> which is t It appears that the severity of dementia shows a closer correlation with the degree of synaptic loss than with the density of senile plaques and neurofibrillary tangles
How does Memantine help "treat" alzheimer's disease?
Memantine is a NMDA glutamate receptor antagonist Rationale: block/ reduce glutamate excitotoxicity
a mutation in what gene would result in early onset of alzheimer ( age 35- 55)
PS1 - also trisomy 21 can result in early onset AD
a mutation in which gene results in Familia AD Volga Germans?
PS2
where in the brain does severe neuronal loss occur in alzheimers disease?
Severe neuronal loss occurs diffusely in the basal nucleus in Alzheimer pt's - Many neurons in the basal ganglia (nucleus) are Cholinergic and send projections to the cerebral cortex - Loss of neurons in the basal ganglia may explain why Alzheimer patients have severely reduced amount of acetylcholine in the cortex Acetylcholine raises the excitability and improves the signal-to-noise ratio of cortical neurons -> enhancing their ability to handle information rapidly and accurately Other transmitters affected in AD - Locus Coeruleus and Raphe Nuceli Which explains why the levels of Norepinephrine and Serotonin in the cortex are markedly reduced
whwhat APP Mutations are assocaited with familial alzhemier's disease?
familila alzheimers disease causes a change stucture of Aβ from nontoxic 40- , to toxic (amyloidogenic) 42-amino acid - which has a greater tendency to form amyloid deposits Aβ normally undergoes enzymatic breakdown by neprilysin (NEP), insulin degrading enzyme or endothelin converging enzyme and is cleared from the brain - but in alzheimer disease Aβ is secreted from neurons and forms precipitates -> amyloid plaques
what is mild cognitive impairment?
is a significant cognitive impairment but fails to meet life-disruptive criterion for AD - AD has more plaques and NFTs than MCI
sporadic forms of Alzheimer's disease is usually due to?
is not due to genetic mutations
what causes Neurofibrillary tangles to form?
neurofibrillary tangle form due to hyper-phosphorylation of Tau Protein - which destabilizes Microtubules in dendrites and axons - Tau hyper-phosphorylation simultaneously disrupts neuronal cytoskeleton and forms extracellular neurofibrillary tangles
describe the current treatment for Alzheimers disease?
the treatment strategy is to slow down the progression of the disese via - Acetylchoinesterase inhibitors - Memantine
how does acetylcholinesterse inhibitors help "treat" alzheimers diseae
they block ACH metabolism in synapse Functions to: - Boost cholinergic neurotransmission in septo-hippocampal system (medial septral nuclei to hippocampus) - Boost cholinergic neurotransmission in cholinergic projections to cerebral cortex from basal nucleus of Meynert and Sub. Innominata - Enhances attention/memory but does not stop neurodegeneration
how does the neurofibrillary tangles contribute to the symptoms of alzheimers?
they degrade the local environment for live cells -> resulting in neuronal cell death
what are neurofibrillary tangles?
thickened intraneuronal fibrils which consist of paired helical filaments (PHF)