Johnson AD

Preclinical AD patho

Abnormal levels of beta amyloid & tau proteins on PET scan & CSF

Symptoms of mild cofgnitive impairment due to AD

Misplacing items, personality changes, trouble remembering names of familiar objects, flat mood

Symptoms of Dementia due to moderate AD

forgetting details about own lide, changes in sleep, confused speech

Symptoms of Dementia due to severe AD

cant understand langauge, will not reecongize familt, cant perform daily living activities

What is ApoE

transports cholesterol and other fats throughout the body may also be involved in the structure and function of the fatty membrane surrounding a brain cell

→APOE-e4 is associated with an increased risk of developing AD

becuase it is the LEAST effective

What is more common sporadic or familial AD and what are the relevant genes and plaques?

Sporadic is more common, APOE-e4 is associated with an increased risk of developing AD

Amyloid Beta plaques

What is pathology of plaques in someone without AD

APP is cleaved by an enzyme called alpha secretase within the Amyloid Beta region, preventing the formation of beta amyloid plaques

What is pathology of plaques in someone with AD

The amyloidogenic pathways involved sequential cleavage of APP by beta secretase (BACE1) and gamma secretase to form Amyloid Beta peptides that aggregate and form plaques

How are aggregates cleared in a person without AD?

Double membrane forms with LC3 as a docking protein on the inner membrane. Surveyors (P63) bind to the misfolded protein and brings them into the autophagosome until it encapsulated all the proteins. Then it fuses with a lysosome and prteases break it down

How are aggregates cleared in a person with AD?

Amyloid beta accumulates in auophagic vesicles. Autophagosome/autolysosomes accumulate in neurons. They start to leak and damage other organelles

Formation of Tau proteins in a person without AD

Tau proteins bind to microtubules to stabilize them in neurons. Tau is a phosphoprotein that undergoes phosphorylation

Formation of Tau proteins in a person with AD

Tau undergoes Hyperphosphorylation which leads to conformational change preventing it from binding to the microtubules. It aggregates into filaments/tangels which disrupt neuron function

How are tau proteins degraded in a perosn without AD

Autophagy system & 26S Proteasome

How are tau proteins degraded in a person with AD

PS1 Mutation disrupts activation of lysosomes and fusion to autophagosomes leading to accumulation of dysfunctional autophagic vacuoles, P62, and Tau aggregates

Affects of Amyloid Beta plauqes and Tau hyperphosphorylation

Accerealte Neurodegeneration

1) Dusrupt Calcium homeostasis

2) Damage mitochondria

3)Chronic inflammation

4) Impaired proteins clearance

5)Synpatic dysfunction

6)Tau hyperphosphorylation—> Tangles

Meds for AD

Aducanumab

AChE inhibitors

NMDA Antagonist

AChE inhibitors

Donepezil

Rivastigmine

Galantamine

Tacrine- NOT USED

NMDA Antagonist

Memantine

Treatment goals of AD

Slow progression

Manage behavior problems

Modify home environment

Support caregiver

Sick Astrocyte Hypothesis & Nef2 Activation

Nrf2 (transcription factor) activation can help sick astrocytes in presence of Amyloid Beta plaques by decreasing oxidative stress

Astrocytic Nrf2 improves:

Protein degredartion

Carb metabolism

Protein translation

Synpatic function

Chronic Traumatic Encephalopahy (CTE)

Amyloid beta deposits + tangles in astrocytes and neurons

Sx: Impulsivity, depression, apathy, anxiety, violence, etc

With one copy of these mutated genes, you WILL get alzheimers

APP(Amyloid precursor protein)

PS1 (Presenilin 1)

PS 2 (Presenilin 2)

___ Cholesterol is a risk factor for getting alzheimers

High

Do all e4 positive people develop Ad?

no

Alzheimers makes up ___ % of the medicare budget

16%

Most drug trials for AD crash at which clinical phase?

Phase 3 clinical trials

Macroautophagy

Alzheimer's disease is characterized by the accumulation of amyloid-beta plaques and tau tangles in the brain. Autophagy helps in the clearance of these plaques and tangles. Impaired autophagy can lead to the accumulation of these toxic proteins, contributing to Alzheimer's pathology.

Accumulation of Amyloid Beta Intracellular

APP localizes in the palsma membrane

APP turnover is mediated by endosomal internalization

Autophagosomes in neurons of AD brain

Overexpression of mutant APP leads to Amyloid Beta peptide

Aducanumab

reduces AB plaques in Alzheimer’s disease

→(Lots of tea)

Ozempic

GLP1 agonist, may help with alzheimers

Hydro Methylthionine Mesylate (HMTM)

methylene blue, tau aggregation inhibitor, failed on both primary endpoints

Amyloid Neta Pathology indices tissue wide deficits in four primary areas that are all rescued by astrocytic Nrf2

1)Protein degradation

2)Carb metabolism (Oxidative phosphorylation, glycolysis)

3)Protein translation

4)Synaptic function