The accumulation of lysosomes and their hydrolases within neurons is a well-established neuropathologic feature of Alzheimer disease (AD). Here we show that lysosomal pathology in AD brain involves extensive alterations of macroautophagy, an inducible pathway for the turnover of intracellular constituents, including organelles. Using immunogold labeling with compartmental markers and electron microscopy on neocortical biopsies from AD brain, we unequivocally identified autophagosomes and other prelysosomal autophagic vacuoles (AVs), which were morphologically and biochemically similar to AVs highly purified from mouse liver. AVs were uncommon in brains devoid of AD pathology but were abundant in AD brains particularly, within neuritic processes, including synaptic terminals. In dystrophic neurites, autophagosomes, multivesicular bodies, multilamellar bodies, and cathepsin-containing autophagolysosomes were the predominant organelles and accumulated in large numbers. These compartments were distinguishable from lysosomes and lysosomal dense bodies, previously shown also to be abundant in dystrophic neurites. Autophagy was evident in the perikarya of affected neurons, particularly in those with neurofibrillary pathology where it was associated with a relative depletion of mitochondria and other organelles. These observations provide the first evidence that macroautophagy is extensively involved in the neurodegenerative/regenerative process in AD. The striking accumulations of immature AV forms in dystrophic neurites suggest that the transport of AVs and their maturation to lysosomes may be impaired, thereby impeding the suspected neuroprotective functions of autophagy.

http://www.aecom.yu.edu/cuervo/images/AD-autophagy%202005%20JNEN.pdf

Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study.

Autophagy is the sole pathway for organelle turnover in cells and is a vital pathway for degrading normal and aggregated proteins, particularly under stress or injury conditions. Recent evidence has shown that the amyloid β peptide is generated from amyloid β precursor protein (APP) during autophagic turnover of APP-rich organelles supplied by both autophagy and endocytosis. Aβ generated during normal autophagy is subsequently degraded by lysosomes. Within neurons, autophagosomes and endosomes actively form in synapses and along neuritic processes but efficient clearance of these compartments requires their retrograde transport towards the neuronal cell body, where lysosomes are most concentrated. In Alzheimer disease, the maturation of autophagolysosomes and their retrograde transport are impeded, which leads to a massive accumulation of `autophagy intermediates9 (autophagic vacuoles) within large swellings along dystrophic and degenerating neurites. The combination of increased autophagy induction and defective clearance of Aβ-generating autophagic vacuoles creates conditions favorable for Aβ accumulation in Alzheimer disease.

Autophagy, amyloidogenesis and Alzheimer disease

Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases

The role of 17 beta-hydroxysteroid dehydrogenases.

Aβ localization in abnormal endosomes: association with earliest Aβ elevations in AD and Down syndrome

Human Brain Short Chain l-3-Hydroxyacyl Coenzyme A Dehydrogenase Is a Single-domain Multifunctional Enzyme: CHARACTERIZATION OF A NOVEL 17β-HYDROXYSTEROID DEHYDROGENASE *

http://cdr.rfmh.org/Publications/PDFs_Nixon/Mathews%202002%20J%20Biol%20Chem-Alzheimer.pdf

Alzheimer's Disease-related Overexpression of the Cation-dependent Mannose 6-Phosphate Receptor Increases Aβ Secretion: ROLE FOR ALTERED LYSOSOMAL HYDROLASE DISTRIBUTION IN β-AMYLOIDOGENESIS

https://www.jbc.org/content/278/9/7135.full.pdf

Pankaj Mehta

Papers

Human Brain Short Chain l-3-Hydroxyacyl Coenzyme A Dehydrogenase Is a Single-domain Multifunctional Enzyme: CHARACTERIZATION OF A NOVEL 17β-HYDROXYSTEROID DEHYDROGENASE *

Alzheimer's Disease-related Overexpression of the Cation-dependent Mannose 6-Phosphate Receptor Increases Aβ Secretion: ROLE FOR ALTERED LYSOSOMAL HYDROLASE DISTRIBUTION IN β-AMYLOIDOGENESIS

Biosynthesis, Glycosylation, and Enzymatic Processingin Vivo of Human Tripeptidyl-peptidase I

Multipotent Embryonic Lung Progenitors: Foundational Units of In Vitro and In Vivo Lung Organogenesis.