-Degeneration of the hippocampal and cortical neurons, especially cholingeric neurons in the cerebral cortex

-10% of patients over 65

-unknown why but may have genetic component to it: presinilin gene (gamma secretase complex) and E4 isoform of the cholesterol transporter apoE has a higher lifetime risk

-see neurofibrillary tangles and amyloid plaques in autopsy 

-Amyloid precursor protein (APP) is like a receptor in which it resides in the cell membrane and has an extracellular, intracellular and transmembrane part. The APP provides nutrients to the cell.

-alpha secretase cleaves at the membrane so it cleaves an extracellular portion (nutritive).

-beta and gamma secretases cleave in two different areas. If we get a peptide with 42 amino acids (or 40) this is called beta amyloid. 

-the beta amyloids will clump together and atrocytes and monocytes might be within this mix

-alzheimers have more beta and gamma secretase than alpha secretase

-we have microtubules that run the lengths of the neuron that provide structure and nutrients to the neurons

-tau molecules stabilize these mircrotubules

-In alzheimers, these tau molecules are phosphorylated and now the phosphorylated taus interact with each other and form tangles

- this distabilizes the microtubules: makes them disintergrate

-beta amyloid plaques stimulates the kinase and causes phosphorylation of tau

-in a clinical study they injected 42 AP to patients, but this caused severe inflammatory response, causing encephalitis, causing many deaths

-now trying to find drugs that act as beta and gamma secretase inhibitors

-hippocampus: involved with memory

cerebral cortex: involved i thinking

-DEMENTIA: loss in memory, reasoning, learning, inability to preform daily tasks

-severity depends on the # of neurofibrillary tangles

-can lead to death due to pneumonia and pulmonary emboli (immobile, cant function on their own)

They ask the patient questions and look at thier progress.

-looking for rapid cognitive impairment

-definitive diagnosis in autopsy 

-tried to use M1 agonists, but couldnt get the same effects as cholinesterase inhibitors

-thought to be that these inhibitors might have other MOAs that we are unaware of

-give central > peripheral anticholingerics (those that cross the BBB)

-modest increase in cognitive function

this drug is an anticholingeric that crosses the blood brain barrier. It is used for motion sickness.

-THIS DRUG HAS ALZHEIMERS symptoms 

-increase the sensitivity of NMDA type glutamate receptors leads to continous receptor activation and reduced cognition: hard to ID a signal from a neuron

-glutamate is also neurotoxic (Ca influx)

-NMDA RECEPTOR ANTAGONIST: reduces neuronal "noise" and increases signal, improves cognitive test scores, improved functioning

-reduces excitotoxicity